Polyprenyl composition or compounds and process for the production thereof

ABSTRACT

A polyprenyl composition consisting essentially of a mixture of polyprenyl compounds represented by the following formula ##STR1## wherein A 1  represents a hydroxyl or acetyloxy group, ##STR2## represents a trans-isoprene unit, ##STR3## represents a cis-isoprene unit, and n is an integer of from 11 to 19, said mixture containing substantial amounts of at least three compounds of formula (I) wherein n represents 14, 15 and 16 respectively as essential ingredients in a total amount of at least 70% by weight based on the weight of the mixture; and new compounds derived from the polyprenyl compounds of formula (I). These composition and compounds are useful for the synthesis of mammalian dolichols. The polyprenyl composition can be prepared by extracting the leaves of Ginkgo biloba or Cedrus deodara with an oil-soluble organic solvent; if required, hydrolyzing the extract; and subjecting the extract to one or more of chromatography, fractional dissolution, fractional refrigerating precipitation and molecular distillation, thereby separating and recovering a fraction having a specified Rf value in silica thin-layer chromatography.

This application is a divisional of Ser. No. 654,526, filed September24, 1984, which is a continuation-in-part application of U.S.application Ser. No. 371,487, filed Apr. 23, 1982, now abandoned, whichin turn is a continuation-in-part of U.S. application Ser. No. 324,636,filed Nov. 24, 1981.

This invention relates to a novel polyprenyl composition or compounds.More specifically, this invention pertains to a novel polyprenylcomposition composed of a mixture of polyprenyl homologs which can beextracted from Ginkgo biloba or Cedrus deodara, novel polyprenylcompounds which can be derived from the aforesaid polyprenyl homologs, aprocess for the production of said polyprenyl composition or compounds,and use of such a composition or compounds in the synthesis of mammaliandolichols.

Dolichols were first isolated in 1960 from human kidneys, pig livers,etc. by J. F. Pennock et al. [see Nature (London), 186, 470 (1960)].Later, they ascertained that the dolichols are a mixture of polyprenolhomologs having the composition of the following general formula##STR4## wherein ##STR5## represents a transisoprene unit, and ##STR6##represents a cis-isoprene unit (the same definitions apply throughoutthe present specification),

and the number j of cis-isoprene units in the above formula generallydistributes between 12 to 18 and three homologs in which j is 14, 15 and16 are present in major proportions [R. W. Keenan et al., BiochemicalJournal, 165, 405 (1977)]. It is also known that dolichols aredistributed widely in mammals, and perform a very important function inmaintaining the lives of organisms. For example, J. B. Harford et al.showed by in vitro tests using the brain white matter of calves or pigsthat exogenous dolichols promote in-take of carbohydrates such asmannose into lipid, and consequently increase the formation ofglycoproteins which are important for maintaining the lives of organisms[Biochemical and Biophysical Research Communication, 76, 1036 (1977)].Since the effect of dolichols to take carbohydrates into lipid isremarkable in mature animals as compared with those in the activelygrowing stage, the action of the dolichols has attracted attention forits possible prevention of aging.

R. W. Keenan et al. state that it is important for organisms whichrapidly keep growing, for example, those in the infant stage, to takedolichols extraneously so as to supplement the dolichols obtained bybiosynthesis within their own body [Archives of Biochemistry andBiophysics, 179, 634 (1977)].

Akamatsu et al. determined the quantity of dolichols in the regeneratedliver of a rat and found that the quantity determined is much smallerthan that in normal liver and the function of the liver tissues tosynthesize glycoproteins is drastically reduced and that the addition ofexogenous dolichols improves the reduced function of glycoproteinsynthesis (published in the 1981 conference of the Japanese Society ofBiochemistry).

In this way, the dolichols are very important substances for organisms,and it is strongly desired to develop their use as medicines orintermediates for their synthesis, cosmetics, etc.

However, since dolichols have hitherto been difficult to obtain,sufficient research works have been impossible. For example, only about0.6 g at most of dolichols can be obtained from 10 kg of pig liverthrough complicated separating procedures [see J. Burgos et al.,Biochemical Journal, 88, 470 (1963)].

On the other hand, it is extremely difficult by the present daytechniques of organic synthesis to produce dolichols by a whollysynthetic process, as can be seen in the light of their complex andunique molecular structure. It would be advantageous if dolichols couldbe obtained by simple synthetic chemical treatments from naturallyoccurring intermediate. Such convenient natural substrances, however,have not been discovered to date. It has been known that polyprenolcompounds can be extracted from various plants, and so far, thefollowing polyprenols have been successfully extracted. ##STR7##

The betulaprenols have a structure similar to the dolichols in that twotrans-isoprene units are connected to the omega-terminal isoprene unitand a cis-isoprene unit is linked to these trans-isoprene units.However, the betulaprenols so far known contain up to six cis-isopreneunits at most, and in order to synthesize dolichols containing homologshaving 14, 15 and 16 cis-isoprene units respectively as major componentsfrom these betulaprenols, it is necessary to link at least 8 isopreneunits while maintaining them in cis-form. This procedure is almostimpossible by the present-day organic synthetic techniques.

Recently, K. Hannus et al. reported that a polyisoprenyl fraction in anamount of about 1% dry weight was isolated from the needles of Pinussylvestris, and the fraction consisted of polyisoprenyl acetates with 10to 19 isoprene units predominantly in the cis-configuration. However,the pinoprenol fraction contains homologs having 15 and 16 isopreneunits as major components, and only traces of homologs with 17, 18 and19 isoprene units which are the main components of mammalian dolichols[Phytochemistry, 13, 2563 (1974)]. The Hannus et al. article does notgive details about the trans- and cis-configurations of the pinoprenolhomologs. Even if the pinoprenol fraction has the same trans- andcis-configurations as mammalian dolichols, it is necessary, forconversion into mammalian dolichols, to link at least two cis-isopreneunits while maintaining them in cis-form and further bond a saturatedisoprene unit to the alpha-terminal. Evidently, this presents greatsynthetic difficulties.

D. F. Zinkel et al. reported that the extracts of Pinus strobus needlescontain a C₉₀ polyprenol containing 18 isoprene units or a homologousseries of polyprenols averaging 18 units [Phytochemistry, 11, 3387(1972)]. Their analysis, however, are based only on NMR and are veryrough. When the inventors of the present application traced thisexperiment, they found that the polyprenol fraction extracted from theneedles of Pinus strobus contains a homolog containing 17 isoprene unitas a major component. In order to synthesize mammalian dolichols fromthe polyprenyl fraction isolated from the needles of Pinus strobus, itis necessary to introduce at least one cis-isoprene unit whilemaintaining it in cis-form, and synthetic difficulties are stillanticipated.

The present inventors searched various plants for polyprenyl compoundswhich have the same number of isoprene units of trans- andcis-configurations as mammalian dolichols and therefore do not require adifficult operation of introducing cis-isoprene units while maintainingthem in the cis-configuration, and analyzed extracts from variousplants. These investigations have led to the surprising discovery thatthe polyprenyl fraction (or composition) extracted from Ginkgo biloba orCedrus deodara shows a very similar distribution of polyprenyl homologsto that of polyprenyl homologs in mammalian dolichols except that itdoes not contain a saturated isoprene unit at the alpha-terminal, andtherefore that the extracted polyprenyl fraction is very suitable as anintermediate for synthesis of mammalian dolichols.

According to one aspect of this invention, there is provided a novelpolyprenyl composition (fraction) consisting essentially of a mixture ofpolyprenyl compounds represented by the following formula ##STR8##wherein A₁ represents a hydroxyl or acetyloxy group, ##STR9## representsa trans-isoprene unit, ##STR10## represents a cis-isoprene unit, and nis an integer of from 11 to 19. said mixture containing substantialamounts of at least three compounds of formula (I) wherein n represents14, 15 and 16 respectively as essential ingredients in a total amount ofat least 70% by weight based on the weight of the mixture.

According to another aspect of the invention, the novel polyprenylcomposition (or fraction) can be produced by extracting the leaves ofGinkgo biloba or Cedrus deodara with an oil-soluble organic solvent; ifrequired, hydrolyzing the extract; and subjecting the extract to one ormore of chromatography, fractional dissolution, fractional refrigeratingprecipitation and molecular distillation, thereby separating andrecovering a fraction which shows an Rf value of from 0.18 to 0.25and/or from 0.50 to 0.55 in thin-layer chromatography (developed 10 cm)carried out on a TLC plate of Merck Co. precoated with silica gel 60F₂₅₄ to a layer thickness of 0.25 mm with a mixture of n-hexane andethyl acetate in a volume ratio of 9:1 as a developing solvent undersuch conditions that solanesyl acetate as a standard substance shows anRf value of from 0.40 to 0.45.

The polyprenyl composition or fraction and the process for itsproduction will be described below in greater detail.

Ginkgo biloba used as a raw material for extraction of the polyprenylfraction in accordance with this invention is a plant belonging toDivision Spermatophyta, Subdivision Gymnospermae, Class Ginkgopsida,Order Ginkgoales, Family Ginkgoaceae which occurs mainly in East Asia,especially Japan, China and Korea. Cedrus deodara, another raw materialused in this invention, is a plant belonging to Division Spermatophyta,Subdivision Gymnospermae, Class Coniferopsida, Order Coniferales, FamilyPinaceae which distributes widely in the Temperate and Frigid Zones. Inthe present invention, the leaves of these plants are used as the rawmaterials.

The leaves of G. biloba or C. deodara which can be used in thisinvention may range from young green leaves to completely yellowedleaves, and the fallen leaves may also be used. The leaves to be treatedby the process of this invention may be used undried or after drying.Generally, the dried leaves are preferred. The degree of drying of theleaves should advantageously correspond to a water content, based on theweight of the dried leaves, of less than about 30%, preferably less thanabout 10%. Preferably, the leaves are extracted after they have beencrushed. This increases the area of contact with the extracting solvent,and results in an increased efficiency of extraction.

The polyprenyl homologs of formula (I) are contained in fairly highconcentrations generally in the form of a free alcohol and/or aceticacid ester. In order to extract the polyprenyl homologs from the leavesof these plants effectively, the use of oil-soluble organic solventscapable of well dissolving the polyprenyl homologs is convenient.

Suitable oil-soluble organic solvents that can be used in this inventionhave a dielectric constant (ε) of not more than 32.7, preferably notmore than 25.0, especially preferably not more than 20.7. Specifically,solvents exemplified below are used either singly or as a mixture of twoor more.

(a) Hydrocarbons such as petroleum ether, pentane, hexane, heptane,benzene, toluene and xylene.

(b) Halogenated hydrocarbons such as chloroform, methylene chloride,carbon tetrachloride, tetrachloroethane, perchloroethylene andtrichloroethylene.

(c) Esters such as methyl acetate, ethyl acetate and ethyl propionate.

(d) Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran anddioxane.

(e) Ketones such as acetone, methyl ethyl ketone diethyl ketone anddiisopropyl ketone.

(f) Alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, andbutyl alcohol.

The solvent should desirably extract the desired polyprenyl compounds offormula (I) selectively with a high efficiency, while permittingminimization of extraction of other substances. From this standpoint,the hydrocarbons, halogenated hydrocarbons, esters, and ethers havinglow polarity such as diethyl ether and diisopropyl ether, and ketonesare especially suitable among the above-exemplified solvents.

The amount of the extracting solvent is not critical, and can be variedwidely depending upon the type of the solvent, the type or condition ofthe leaves to be extracted, etc. Generally, it is advantageous that thesolvent is used in an amount of about 1 to about 100 parts by weight,preferably 5 to 50 parts by weight, more preferably 10 to 30 parts byweight, per part (based on the dry weight) of the leaves of Gingkobiloba or Cedrus deodara.

The extraction can be carried out by dipping the leaves in the solvent,and if required, stirring the solvent continuously or intermittently.The temperature during the extraction is neither critical, and can bevaried widely depending upon the extracting conditions such as the typeor amount of the solvent used. Generally, the extracting temperature isfrom about 0° C. to the refluxing temperature of the solvent. Usually,room temperature suffices. Advantageously, under these conditions, theextraction can be carried out for a period of 1 to 10 days.

After the extracting treatment, the leaves and other solid componentsare removed from the dipping solution and if required, the solvent isremoved to form a concentrate. The extract is subjected to a separatingstep consisting of one or more of chromatography, fractionaldissolution, fractional refrigerating precipitation and moleculardistillation, whereby the desired polyprenyl fraction is recovered.

In the separating step, the formation of the fraction of polyprenylcompounds is confirmed by determining whether a spot exists at an Rfvalue of from 0.18 to 0.25 [when A₁ in formula (I) represents a hydroxylgroup] and/or from 0.50 to 0.55 [when A₁ in formula (I) represents anacetyloxy group] in thin-layer chromatography which is carried out on aTLC plate of Merck Co. precoated with silica 60F₂₅₄ to a layer thicknessof 0.25 mm with a mixture of n-hexane and ethyl acetate in a volumeratio of 9:1 as a developing solvent (developed 10 cm) under suchconditions that solanesyl acetate as a standard substance shows an Rfvalue of from 0.40 to 0.45 in the thin-layer chromatography. It shouldbe understood that in the following description, the Rf values ofthin-layer chromatography denote those which are measured under theaforesaid conditions unless otherwise specified.

The operations of the chromatography, fractional dissolution, fractionalrefrigerating precipitation and molecular distillation used in the stepof separating the aforesaid extract are known per se, and in the presentinvention, too, these methods can be carried out in accordance withknown procedures. For the details of these methods, literaturereferences will be cited in lieu of describing them at length. Onlythose items which need special care will be described below.

(A) Chromatography

For details, reference may be made to H. Heftman "Chromatography",Reinhold Publishing Co., New York (1961).

When the amount of the extract is small, thin-layer chromatography orliquid chromatography is suitable. For treatment of a large amount ofthe extract, column chromatography is suitable.

Examples of suitable chromatography carriers are silica gel, alumina,Florisil, Celite, activated carbon, and cellulose. Silica gel isespecially preferred.

Examples of the developing solvent used in the separating operation on asilica gel column include hexane/ethyl acetate (volume ratio from 98:2to 80:20), hexane/diisopropyl ether (volume ratio from 95:5 to 80:20),petroleum ether/methyl acetate (volume ratio from 98:2 to 80:20),petroleum ether/isopropyl alcohol (volume ratio from 99:1 to 90:10),benzene/diethyl ether (volume ratio from 95:5 to 80:20), benzene/ethylacetate (volume ratio from 98:2 to 80:20), and chloroform.

(B) Fractional dissolution

For details, reference may be made to L. C. Craig, "Technique of OrganicChemistry", Vol. 3, Interscience (1951).

The polyprenyl compounds of formula (I) are easily soluble in non-polarsolvents such as pentane and hexane, but are sparingly soluble in polarsolvents such as methanol or water. Hence, the polyprenyl compounds offormula (I) can be purified by the fractional dissolving methodutilizing differences in solubility in these solvents. For example, acrude product such as a concentrate of the extract is dissolved in theaforesaid nonpolar solvent, and then washed with a polar solvent whichis immiscible with the nonpolar solvent, whereby impurities easilysoluble in the polar solvent can be drastically removed. Suitablenonpolar solvents used in this method are, for example, hydrocarbonssuch as petroleum ether, pentane, hexane, heptane, benzene and tolueneand halogenated hydrocarbons such as methylene chloride and chloroform.Suitable polar solvents immiscible with such nonpolar solvents are, forexample, water and methanol.

(C) Fractional refrigerating precipitation

For details, reference may be made to E. W. Berg, Physical and "ChemicalMethods of Separation", Chapter 14 and 15, McGraw-Hill, New York (1963).

The polyprenyl compounds of formula (I) solidify at about -10° C. orless. Hence, the polyprenyl compounds of formula (I) can be purified byallowing the extract to stand at a temperature of not more than -10° C.,preferably -15° to -30° C., to solidify the desired compounds, andremoving the impurities which do not solidify at these temperatures by asolid-liquid separating technique. The polyprenyl compounds, however, donot have good crystallinity and become a waxy solid. Accordingly, theyare difficult to purify completely only by this method. Preferably,therefore, this method is used in combination with another purifyingmethod.

(D) Molecular distillation

For details, reference may be made to G. Burrows, "MolecularDistillation", Clarendon Press, Oxford (1960).

Since the compounds of formula (I) have a high molecular weight, theycan be separated from low-molecular-weight impurities by the moleculardistillation method. For example, the extract is subjected to moleculardistillation at 100° to 250° C. under a vacuum of 10⁻³ to 10⁻⁵ mmHg todivide it into a low-molecular-weight fraction and ahigh-molecular-weight fraction. The desired compounds are retained inthe high-molecular-weight fraction, and the low-molecular-weightimpurities can be removed effectively.

When a sufficiently pure polyprenyl fraction cannot be obtained by eachof these separating methods, two or more of these separating methods maybe used in combination. For example, there can be used a combination ofchromatography and fractional dissolution, a combination ofchromatography, fractional refrigerating precipitation and fractionaldissolution, a combination of chromatography, fractional refrigeratingprecipitation, fractional dissolution and molecular distillation, acombination of chromatography, molecular distillation and fractionaldissolution, a combination of chromatography and molecular distillation,a combination of molecular distillation and fractional dissolution, anda combination of molecular distillation, fractional dissolution andfractional refrigerating precipitation.

As a result of the separating step, a fraction having an Rf value offrom 0.18 to 0.25, and/or from 0.50 to 0.55 in thin-layer chromatographycan be isolated and recovered. The fraction having an Rf value of 0.18to 0.25 consists essentially of a mixture of homologs of formula (I) inwhich A₁ represents a hydroxyl group, and the fraction having an Rfvalue of from 0.50 to 0.55 consists essentially of homologs of formula(I) in which A₁ represents an acetyloxy group.

The resulting fraction can be separated into the individual homologs bysubjecting it further, for example, to high-performance partition liquidchromatography.

Prior to submitting the extract to the aforesaid separating operation,the extract may be hydrolyzed as required to convert homologs of formula(I) in which A₁ represents an acetyloxy group into homologs of formula(I) in which A₁ represents a hydroxyl group. Of course, the hydrolysismay also be carried out on a fraction having an Rf value of 0.50 to 0.55obtained by the separating operation. The hydrolysis can be performed byany usual methods known in the hydrolysis of known fatty acid esters.For example, about 5 to about 50 parts by weight of the extract or thefraction is added to 100 parts by weight of a solution of sodiumhydroxide or potassium hydroxide in aqueous methanol or ethanol (thealkali metal hydroxide concentration of preferably about 0.1 to 30% byweight), and reacted at about 25° to 90° C. for about 0.5 to 5 hours.

In the polyprenyl fraction separated and recovered by the methoddescribed hereinabove, the fraction having an Rf value of 0.18 to 0.25consists essentially of a mixture of polyprenol homologs in which A₁represents a hydroxyl group, and the fraction having an Rf value of 0.50to 0.55 consists essentially of a mixture of polyprenyl acetate homologsof formula (I) in which A₁ represents an acetyloxy group. The ratio ofthe former to the latter in the extract is in the range of from 1:100 to1:5. The distribution pattern of the polyprenol or polyprenyl acetatehomologs is nearly the same for these fractions. The distributionpattern is nearly constant irrespective of the type of the plant used asa raw material, the stage of growth of the leaves, the time ofharvesting, the region of growth, etc.

The fraction generally contains substantial amounts of at least threecompounds, i.e. a compound of formula (I) in which n is 14 (to bereferred to as polyprene-14), a compound of formula (I) in which n is 15(to be referred to as polyprene-15), and a compound of formula (I) inwhich n is 16 (to be referred to as polyprene-16). The total amount ofthe three compounds is at least 70% by weight, preferably at least 75%by weight, based on the weight of the fraction.

Generally, the fraction contains polyprene-15 in the highest proportion.The content of polyprene-15 is usually 30 to 50% by weight, typically 32to 47% by weight, based on the weight of the fraction.

Generally, the fraction contain polyprene-14, polyprene-15 andpolyprene-16 in a unique quantitative relation. Let the contents ofthese compounds be a, b and c% by weight respectively, the quantitativerelation is usually b>a>c.

The fraction contains generally 20 to 35% by weight, typically 23 to 32%by weight, or polyprene-14, and generally 10 to 25% by weight, typically11 to 20% by weight, of polyprene-16.

The polyprenyl composition (or fraction) provided by this invention ischaracteristic in that the distribution pattern of polyprenol homologsis very similar to that of mammalian dolichols, that is the distributionpattern of n in formula (I) is very similar to that of j in formula (A).The distribution pattern of the polyprenol homologs is shown belowagainst that of pig dolichols (the distribution pattern of humandolichols is much the same as that of pig dolichols). The parenthesizedfigures show typical ranges.

                  TABLE 1                                                         ______________________________________                                                     Content (wt. %)                                                  n in formula (I)                                                                             Polyprenyl composi-                                            and j in formula (A)                                                                         tion of the invention                                                                        Pig dolichols                                   ______________________________________                                        11             0-3 (0-2)      0.43                                            12             0.1-6 (0.1-6)  0.60                                            13             4-17 (5-14)    4.38                                            14             20-35 (23-32)  25.59                                           15             30-50 (32-47)  46.01                                           16             10-25 (11-20)  18.79                                           17             2-10 (2-6)     3.41                                            18             0.1-5 (0.1-2)  0.72                                            19             0-3 (0-1.5)    0.06                                            ______________________________________                                    

The polyprenyl composition provided by this invention does notsubstantially contain components other than the polyprenyl homologs offormula (I) shown in Table 1 above, and the average value of n isusually in the range of from 14.25 to 15.25.

As can be seen from the distribution pattern of the polyprenyl homologsshown in Table 1 and from a comparison of formula (I) with formula (A),the polyprenyl composition provided by this invention can be convertedto mammalian dolichols by linking one saturated isoprene unit to thealpha-end of each of the polyprenyl compounds in the composition. Theproblem of cis- or trans-configuration requires no consideration inregard to the saturated isoprene unit to be linked, and in linking thesaturated isoprene unit, no difficulty arises in the reaction operation.Accordingly, the polyprenyl composition provided by this invention is avery important intermediate for the synthesis of mammalian dolichols.

In converting the polyprenyl composition of the invention into mammaliandolichols, the composition may be used as such, or as required, afterthe composition has been separated into the individual polyprenylcompounds. It should be understood therefore that although the followingdescription refers to reactions of the polyprenyl compounds of formula(I), it may be read by replacing the polyprenyl compounds by thepolyprenyl composition having the aforesaid distribution pattern.

In converting the polyprenyl compounds of formula (I) into the dolicholsof formula (A), the compounds of formula (I) may be reacted with areagent for introduction of a saturated isoprene unit, either as such orafter A₁ in formula (A) has been replaced by another reactive leavingatom or group.

Thus, according to still another aspect of this invention, there isprovided a process for producing a mammalian dolichol or its precursorof the following formula ##STR11## wherein Z represents a group of theformula --CH₂ OH or its functional precursor group, n is an integer of11 to 19, ##STR12## represents a trans-isoprene unit, and ##STR13##represents a cis-isoprene unit, which comprises reacting a polyprenylcompound of the following general formula ##STR14## wherein X representsa leaving atom or group, n is as defined above, and the expression ofthe trans- and cis-isoprene units is as defined above,

with a compound of the general formula ##STR15## wherein Y represents alithium atom or MgHal in which Hal is a halogen atom, and Z is asdefined above,

to form a compound of formula (V); and when Z represents the functionalprecursor group, converting it, if required, into --CH₂ OH.

The leaving atom or group X in formula (III) includes not only ahydroxyl group and an acetyloxy group, but also any other atoms orgroupings which have the property of being split off by reaction withthe MgHal or lithium atom Y, whereby they perform substitution reactionwith the carbon atom to which Y is bonded, on the carbon atom to which Xwas bonded. Preferably, such leaving atom or group is selected from theclass consisting of halogen atoms and groups of the formulae --OCOR₁,--OR₂, --OPO(OR₃)₂, --SOR₃, --SO₂ R₃, --OCOOR₃, ##STR16##

In the above formulae, R₁ represents a hydrogen atom, a methyl groupsubstituted by 1 to 3 fluorine or chlorine atoms, an alkyl or alkenylgroup having 2 to 18 carbon atoms, an aryl group having 6 to 10 carbonatoms or an aralkyl group having 7 to 11 carbon atoms; R₂ represents alower alkyl group, a lower alkenyl group, an aryl group having 6 to 10carbon atoms, a pyridyl group, a thiazolyl group, a thiazolinyl group,or an oxazolyl group; R₃ represents a lower alkyl group, an aryl grouphaving 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbonatoms; O represents an oxygen or sulfur atom; and Hal represents ahalogen atom.

In the present specification and the appended claims, the term "lower"as used to qualify a group or a compound means that the group orcompound so qualified has up to 8 carbon atoms, preferably up to 4carbon atoms.

Examples of the "methyl group substituted by 1 to 3 fluorine or chlorineatoms" in the above definition are --CH₂ F, --CHF₂, --CF₃, --CH₂ Cl,--CHCl₂, and --CCl₃, and --CH₂ F, --CF₃, and --CH₂ Cl are preferred.

The alkyl and alkenyl groups may be linear, branched linear, or cyclic.Examples of the alkyl group are methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, n-hexyl,n-octyl, n-decyl, n-dodecyl, n-undecyl, stearyl, cyclopentyl,cyclohexyl, and cycloheptyl. Examples of the alkenyl group include3-butenyl, 3-pentenyl, 4-pentenyl, geranyl, farnesyl, and oleyl.

The "alkyl or alkenyl groups having 2 to 18 carbon atoms" represented byR₁ are preferably alkyl groups having 2 to 6 carbon atoms and alkenylgroups having 4 to 6 carbon atoms. As the "lower alkyl group" and the"lower alkenyl group" represented by R₂ and R₃ respectively, methyl,ethyl, n-propyl, i-propyl and butyl, and vinyl and 3-butenyl areespecially preferred.

The "aryl groups having 6 to 10 carbon atoms" include a phenyl group, aphenyl group whose benzene ring is substituted by 1 to 3 lower alkylgroups, such as tolyl or xylyl, and a naphthyl group. The "aralkylgroups having 7 to 11 carbon atoms" include lower alkyl groupssubstituted by a substituted or unsubstituted phenyl group, such asbenzyl, phenethyl, methylbenzyl, dimethylbenzyl, alphanaphthylmethyl,and beta-naphthylmethyl.

Preferred leaving atoms or groups represented by X in formula (III)include the following atoms or groups in addition to a hydroxyl groupand an acetyloxy group.

(a) Halogen atoms such as chlorine, bromine or iodine atom.

(b) Groups of the formula --OCOR₁, such as formyl, mono-fluoroacetyloxy,trifluoroacetyloxy, monochloroacetylloxy, propionyloxy, butyryloxy,stearoyloxy, benzoyloxy, 3,5-dimethylbenzoyloxy, and 4-ethylbenzoyloxy.

(c) Groups of the formula --OR₂ such as methoxy, ethoxy, phenoxy,2-pyridyloxy, 2-benzothiazolyloxy, 2-benzoxazolyloxy, trimethylsilyloxy,dimethyl t-butylsilyloxy, methylthio, ethylthio, phenylthio, tolylthio,2-thiazolinylthio, 2-benzothiazolylthio, 2-benzoxazolylthio, and2-pyridylthio.

(d) Groups of the formula --OPO(OR₃)₂ such as dimethylphosphonoxy,diethylphosphonoxy, and diphenylphosphonoxy.

(e) Groups of the formula --SOR₃ such as methylsulfinyl, ethylsulfinyl,propylsulfinyl, phenylsulfinyl and 4-tolylsulfinyl.

(f) Groups of the formula --SO₂ R₃ such as methylsulfonyl,ethylsulfonyl, propylsulfonyl, phenylsulfonyl, and 4-tolylsulfonyl.

(g) Groups of the formula --OCO₂ R₃ such as methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, phenoxycarbonyloxy, and4-tolyloxycarbonyloxy.

(h) Groups of the formula ##STR17## such as N,N-dimethylcarbamoyloxy,N,N-diethylcarbamoyloxy, N,N-dipropylcarbamoyloxy,N,N-diphenylcarbamoyloxy, and N-phenyl-N-ethylcarbamoyloxy.

(i) Groups of the formula ##STR18## such as trimethylammonium bromide,triethylammonium iodide and diphenylethylammonium bromide.

(j) Groups of the formula ##STR19## such as dimethylsulfonium bromide,diethylsulfonium iodide, dipropylsulfonium bromide, andphenylethylsulfonium bromide.

When the compound of formula (III) is used in an isolated form, n informula (III) is preferably 15.

In the compound of formula (IV) to be reacted with the compound offormula (III), Z represents a group of the formula --CH₂ OH or itsfunctional precursor group. The functional precursor group includeshydroxymethyl and aldehyde groups protected by protective groups whichcan be easily split off by such treatments as hydrolysis orhydrogenolysis. The aldehyde group, after deprotection, can be convertedto a hydroxymethyl group by subjecting it to mild reducing conditions,for example reduction with a complex metal hydride such as sodiumborohydride, lithium borohydride, lithium aluminum hydride, sodiumaluminum hydride.

Specific examples of such functional precursor groups are shown below.

(1) Groups of the formula --CH₂ O--R₄ wherein R₄ represents a loweralkyl group, an aralkyl group having 7 to 11 carbon atoms, an aliphaticor alicyclic ether residue having 1 to 8 carbon atoms, or a silyl groupof the formula ##STR20## in which each of R₅₁, R₅₂, and R₅₃ represents alower alkyl group, a phenyl group, a tolyl group or a xylyl group.Examples are as follows: ##STR21##

(2) Groups of the formula ##STR22## wherein Q₁ and Q₂ each represent anoxygen or sulphur atom, and R₆₁ and R₆₂ each represent a lower alkylgroup, or when taken together, represent a lower alkylene group.

Examples are as follows: ##STR23##

Most of the compounds of formula (IV) are known, and those which arenovel can be easily produced in accordance with the methods forproducing the known compounds.

The reaction between the compounds of formula (III) and the compound offormula (IV) can be carried out by methods known per se. For example,the reaction can be carried out in an inert organic solvent. Typicalexamples of the solvent are ethers such as diethyl ether, diisopropylether, dioxane, tetrahydrofuran, dimethoxyethane, and diethylene glycoldimethyl ether. It is also possible to use a mixture of such an etherwith a small amount of hydrocarbon such as hexane and benzene, orhexamethylphosphoramide. Tetrahydrofuran is an especially suitablesolvent.

The ratio between the compounds of formula (III) and formula (IV) is notcritical, and can be broadly varied depending upon the types of thecompound of formula (III) and/or the compound of formula (IV), etc.Generally, the compound of formula (IV) is used in a proportion of 0.5to 10 moles, preferably 1 to 6 moles, especially preferably 1.5 to 4moles, per mole of the compound of formula (III).

The reaction can be carried out in the presence or absence of acatalyst.

When no catalyst is used, the reaction is advantageously carried out ata temperature of generally from about 0° C. to the refluxing temperatureof the reaction mixture, preferably from about 0° C. to about 80° C.Advantageously, the starting compound of the formula (III) is the one inwhich X represents a halogen atom, --OPO(OR₃)₂, an oxazolyloxy group, ora pyridyloxy group.

The catalyst which may be used in the above reaction is, for example, acopper catalyst, a nickel catalyst or a palladium catalyst. Examples ofthe copper catalyst are copper (I) compounds such as CuCl, CuBr, CuI andCuOAc, and copper (II) compounds such as Li₂ CuCl₄, CuCl₂, CuBr₂, CuI₂,CU(OAc)₂, and Cu(CH₃ COCHCOCH₃)₂. Examples of the nickel catalyst arenickel complexes, and nickel (II) compounds such as NiCl₂, NiBr₂, NiI₂,Ni(NO₃)₂, and Ni(CH₃ COCHCOCH₃)₂. Examples of the palladium catalyst arepalladium complexes, and palladium (II) compounds such as PdCl₂,Pd(OAc)₂, Pd(NO₃)₂, and Pd(CH₃ COCHCOCH₃)₂.

When a compound of formula (IV) in which Y is MgHal is used as thestarting material, copper (I) or (II) compounds are preferred as thecatalyst. When a compound of formula (IV) in which Y is a lithium atomis used as the starting material, copper (I) compounds are preferred asthe catalyst. The amount of such a copper catalyst is generally 0.001 to1.0 equivalent, preferably 0.001 to 0.1 equivalent, per mole of thecompound of formula (III) in the case of the former, and 1 to 5equivalents, preferably 1.2 to 3 equivalents, per mole of the compoundof formula (III) in the case of the latter.

The suitable reaction temperature used in the reaction of the compoundof formula (III) with the compound of formula (IV) in the presence ofthe above catalyst is generally from -30° C. to +30° C., preferably from-20° C. to +20° C.

Preferred species of X in the starting compound of formula (III) areacetyloxy, --OCOR₁, --OCOOR₃, ##STR24## oxazolyloxy, and pyridyloxy.

If the catalyst is used in too large an amount, and/or the reaction iscarried out at too high a temperature, an isomer of the compound offormula (V), which is expressed by the following formula ##STR25##

wherein Z and n are as defined above, may occur as a by-product. It isimportant therefore to select conditions which can minimize formation ofthis isomer.

By the above reaction, a compound of the following formula ##STR26##

wherein Z and n are as defined hereinabove, can be obtained in goodyields. This compound can be separated from the reaction mixture andpurified by methods known per se, for example by silica gel or aluminachromatography, fractional dissolution, or molecular distillation.

Removal of the protective group from the compound of formula (V) can beeffected by hydrolyzing or hydrogenolyzing it in accordance with methodsknown per se.

For example, when Z represents --CH₂ --O--R₄ and R₄ represents a loweralkyl group, the compound of formula (V) may be deprotected by treatingit with iodotrimethylsilane in a solvent such as tetrahydrofuran,chloroform or methylene chloride at room temperature. Whe R₄ in theabove formula --CH₂ --O--R₄ represents an aralkyl group, the protectivegroup may be removed by adding a tetrahydrofuran solution of thecompound of formula (V) dropwise to a solution of lithium in ethylamine,and after the reaction, decomposing lithium with, for example, asaturated aqueous solution of ammonium chloride. When R₄ in the aboveformula represents an ether residue, the protective group may be removedby dissolving the compound of formula (V), for example, in a mixedsolvent of hexane/ethanol (about 1/1), adding pyridiniump-toluenesulfonate (preferably in an amount of about 0.1 to 0.2equivalent) to the solution, reacting the mixture at about 50° to 60° C.for several hours, and after the reaction, neutralizing the reactionmixture with sodium carbonate or the like. When R₄ in the above formularepresents a silyl group, the deprotection may be carried out by addingtetra-n-butyl ammonium fluoride (preferably in an amount of about2-equivalents) to a tetrahydrofuran solution of the compound of formula(V), and stirring the mixture overnight at room temperature.

When Z represents ##STR27## and Q₁ and Q₂ do not simultaneouslyrepresent a sulfur atom, Z may be converted to an aldehyde group (--CHO)by treating the compound of formual (V) with dilute hydrochloric acid(preferably about 10% HCl), etc. in a solvent such as tetrahydrofuran orisopropanol. When Q₁ and Q₂ in the above group simultaneously representsulfur atoms, Z may be converted to the aldehyde group by adding atleast an equivalent of HgCl₂, CdCO₃ and a small amount of water to anacetone solution of the compound of formula (V) and reacting them atroom temperature for several hours.

The aldehyde group so converted can be converted to a hydroxymethylgroup (--CH₂ OH) by reducing it under mild reducing conditions, forexample reducing it with a complex metal hydride such a sodiumborohydride, lithium borohydride, lithium aluminum hydride or a sodiumaluminum hydride. The reduction can be carried out by methods known perse. For example, when sodium borohydride is used as the reducing agent,the reaction is desirably carried out at about 0° C. to room temperaturein a solvent such as alcohol, tetrahydrofuran or ether. When lithiumborohydride, lithium aluminum hydride or sodium aluminum hydride is usedas the reducing agent, the reducing reaction is advantageously carriedout at about -30° C. to room temperature in an anhydrous solvent such asanhydrous diethyl ehter or tetrahydrofuran.

After the reducing reaction, the reaction mixture is treated with water,alcohol, ethyl acetate, etc. to decompose the excess of the reducingagent, and separated and purified in a usual manner to give the desiredalcohol (the compound of formula (V) in which Z is a hydroxymethylgroup) in high yields.

The mammalian dolichols synthesized by the above procedure are useful asvaluable biologically active compounds in the fields of medicines andcosmetics.

Compounds of formula (III) in which X represents a leaving atom or groupother than the hydroxyl and acetyloxy groups, that is, polyprenylcompounds of the following formula ##STR28## wherein A₂ represents ahalogen atom or a group of the formula ##STR29## in which R₁ representsa hydrogen atom, a methyl group substituted by 1 to 3 fluorine orchlorine atoms, an alkyl or alkenyl group having 2 to 18 carbon atoms,an aryl group having 6 to 10 carbon atoms or an aralkyl group having 7to 11 carbon atoms, R₂ represents a lower alkyl group, a lower alkenylgroup, an aryl group having 6 to 10 carbon atoms, a pyridyl group, athiazolyl group, a thiazolinyl group, or an oxazolyl group, R₃represents a lower alkyl group, an aryl group having 6 to 10 carbonatoms, or an aralkyl group having 7 to 11 carbon atoms, O represents anoxygen or sulfur atom, and Hal represents a halogen atom; ##STR30##represents a transisoprene unit; ##STR31## represents a cis-isopreneunit; and n is an integer of 11 to 19, are novel compounds not describedin the prior literature. Conversion of the compounds of formula (I) tothe compound of formula (II), that is, the conversion of A₁ in formula(I) to A₂ in formula (II), can be preformed by methods known per se.Some examples are shown below.

(1) Compound of formula (II) in which A₂ is a halogen atom:

This compound can be obtained by halogenating a compound of formula (I)in which A₁ represents a hydroxyl group with a halogenating agent suchas phosphorus trihalide or thionyl halide. The halogenation may becarried out in a solvent such as hexane or diethyl ether in the absenceor presence of a base such as pyridine or triethylamine at a temperatureof about -20° C. to about +50° C. by adding the above halogenating agentdropwise.

(2) Compound of formula (II) in which A₂ represents --OCOR₁ :

This compound can be produced by esterification or ester-exchangereaction of a compound of formula (I) in which A₁ represents a hydroxylgroup. The esterification can be carried out, for example, by reactingthe compound of formula (I) with a desired acid anhydride or halide(preferably in an amount of about 1 to about 5 equivalents) in thepresence of about 1 to about 10 equivalents of pyridine at a temperatureof about -30° C. to about +50° C.

(3) Compound of formula (II) in which A₂ is --OR₂ :

This compound can be obtained by the reaction of an alcohol or thiol offormula R₂ OH with the compound of formula (II) in which A₂ represents ahalogen produced by the method described in paragraph (1) above, in thepresence of a base. A compound of formula (II) in which A₂ is --OR₂ andO is an oxygen atom can also be obtained by the reaction of a halide orformula R₂ Hal (in which Hal is a halogen atom) with the compound offormula (I) in which A₁ is a hydroxyl group.

Generally, the above reaction can be carried out by treating thestarting compound with the alcohol or thiol or the halide in a solventsuch as dimethyl formamide or tetrahydrofuran in the presence of a basesuch as sodium hydride or n-butyl lithium at room temperature or undercooling.

(4) Compound of formula (II) in which A₂ represents --OPO(OR₃)₂ :

This compound can be obtained by reacting a compound of formula (I) inwhich A₁ represents a hydroxyl group with a phosphorochloridate of theformula ClPO(OR₃)₂ in a solvent such as chloroform or methylene chloridein the presence of an approximately equivalent or larger amount ofpyridine at a temperature of usually about 0° C. to room temperature.

(5) Compound of formula (II) in which A₂ represents --SOR₃ :

This compound can be produced by oxidizing the compound of formula (II)in which A₂ represents --SR₂ produced as described in paragraph (3)above, with a slight excess of an oxidizing agent such as sodiumperiodate or aqueous hydrogen peroxide. The oxidation can usually becarried out at room temperature in aqueous methanol, aqueous acetone,etc.

(6) Compound of formula (II) in which A₂ is --SO₂ R₃ :

This compound can be obtained by reacting a compound of formula (II) inwhich A₂ is a halogen atom produced as described in paragraph (1) above,with a compound of the formula R₃ SO₂ Na in a solvent such as dimethylformamide or tetrahydrofuran at room temperature to about 70° C.

(7) Compound of formula (II) in which A₂ is --OCO₂ R₃ :

This compound can be obtained by reacting a compound of formula (I) inwhich A₁ is a hydroxyl group with a haloformate ester of the formulaHalCO₂ R₃ in the presence of a base such as pyridine.

(8) Compound of formula (II) in which A₂ is ##STR32##

This compound can be produced by reacting a compound of formula (I) inwhich R₁ represents a hydroxyl group with a carbamoyl halide of theformula ##STR33## at a temperature of about 0° C. to room temperature ina suitable solvent in the presence of a base such as butyllithium.

(9) Compound of formula (II) in which A₂ is ##STR34##

This compound can be obtained by reacting the compound of formula (II)in which A₂ is a halogen (Hal) produced as described in paragraph (1)above, with a large excess of an amine of the formula ##STR35##generally at room temperature.

(10) Compound of formula (II) in which A₂ is ##STR36##

This compound can be produced by reacting the compound of formula (II)in which A₂ is --SR₃ produced as described in paragraph (3) above, withan alkyl halide of the formula R₃ Hal, or by reacting the compound offormula (II) in which A₂ is a halogen produced as described in paragraph(1) above, with a sulfide of the formula R₃ --S--R₃.

The following examples illustrate the present invention morespecifically.

In these examples, IR analysis was carried out by using a liquid filmfor oily products and a KBr tablet for solid products. The NMR analysiswas carried out by using TMS as an internal standard. The results ofField Desorption Mass Spectrometry (FD-MASS) analysis were corrected for¹ H, ¹² C, ¹⁴ N, ¹⁶ O, ¹⁹ F, ²⁸ Si, ³¹ P, ³² S, ³⁵ Cl, ⁷⁹ Br.

EXAMPLE 1

Five kilograms (in the undried state) of the yellowed leaves of Ginkobiloba collected in Tokyo from late autumn to early winter were crushedinto small fragments by a mixer, and then extracted with 100 liters of amixed solvent of petroleum ether/acetone (4:1 by volume) at about 20° C.The extract was washed with water and dried over anhydrous sodiumsulfate. The solvent was distilled off to give about 100 g of a residue.One liter of n-hexane was added to the residue to dissolven-hexane-soluble components. The solution was filtered, and the filtratewas concentrated and subjected tossilica gel column chromatography usingn-hexane/diethyl ether (95/5 by volume) as an eluent to separate afraction having an Rf value of 0.52 as determined by silica gelthin-layer chromatography (TLC plate silica gel 60F₂₅₄ precoated, layerthickness 0.25 mm, made by Merck Co.; developed 10 cm) using a mixedsolvent of n-hexane/ethyl acetate (9/1 by volume) as a developingsolvent. Thus, about 17 g of anooily product was obtained. In the abovethin-layer chromatography, solanesyl acetate had an Rf of 0.41.

The oily product was heated at 65° C. for 2 hours together with 200 mlof methanol, 20 ml of water and 10 g of sodium hydroxide. Methanol wasthen distilled off, and 300 ml of diethyl ether was added to the residueto perform extraction. The ethereal layer was washed with about 50 ml ofwater five times, and dried over anhydrous sodium sulfate. The solventwas distilled off to give 10.3 g of an oily product. The oily productwas found to be a polyprenol fraction having a purity of more than 95%.This product was subjected to high-performance liquid chromatographyusing μ-Bondapak-C₁₈ (silica gel surface-treated with a C₁₈ hydrocarboncompound) as a packing material, a mixed solvent of acetone/methanol(90/10 by volume) as a developing solvent and a differentialrefractometer as a detector, and the area proportions of the individualpeaks in the resulting chromatography were determined. The results areshown in Table 5.

The individual components were separated from the above oily product(containing more than 95% of polyprenols) by using a high-performanceliquid chromatography column (C₁₈ type) RP 18-10 for semipreparativechromatography (made by Merck Co.) and a mixed solvent ofacetone/methanol (90/10 by volume) as a developing solvent. By massspectroscopy, infrared absorption spectroscopy, ¹ H-NMR spectroscopy and¹³ C-NMR spectroscopy, these compounds were determined to be polyprenolshaving the structure represented by general formula (I).

The results of FD-MASS of these components and their δ values in ¹ H-NMRspectra are summarized in Table 2. The δ values of these components in¹³ C-NMR spectra are summarized in Table 3.

In the ¹ H-NMR data, (b) represents a broad signal; (d), a doubletsignal; and (t), a triplet signal.

    TABLE 2      n .sup.1 HNMR δ(ppm)          units)isoprenecis-(number of      FoundCald.(m/e)FD-MASS C.sub.--HCH.sub.2 OH C.sub.--H C.sub.--H .sub.2     OH C.sub.--H.sub.2      ##STR37##      ##STR38##      ##STR39##        11 970 970 5.44 (t) 5.13 (b) 4.08 (d) 2.04 (b) 1.74 1.68 1.60 12 1038     1038 5.44 (t) 5.12 (b) 4.08 (d) 2.04 (b) 1.74 1.68 1.60 13 1106 1106     5.43 (t) 5.12 (b) 4.08 (d) 2.04 (b) 1.74 1.68 1.60 14 1174 1174 5.44 (t)     5.12 (b) 4.08 (d) 2.04 (b) 1.74 1.68 1.60 15 1242 1242 5.44 (t) 5.13 (b)     4.08 (d) 2.04 (b) 1.74 1.68 1.60 16 1310 1310 5.44 (t) 5.14 (b) 4.08 (d)     2.04 (b) 1.74 1.68 1.60 17 1378 1378 5.44 (t) 5.13 (b) 4.08 (d) 2.04 (b)     1.74 1.68 1.60 18 1446 1446 5.43 (t) 5.13 (b) 4.08 (d) 2.05 (b) 1.74     1.68 1.60 19 1514 1514 5.44 (t) 5.13 (b) 4.08 (d) 2.04 (b) 1.74 1.68     1.60

                                      TABLE 3                                     __________________________________________________________________________     .sup.13 C-NMR δ(ppm)                                                    units)isopreneof cis-numbern                                                       ##STR40##                                                                         CH   .sub.--CH.sub.2 OH                                                                 ##STR41##                                                                                ##STR42##                                                                               ##STR43##                            __________________________________________________________________________    11   135.17                                                                            125.09                                                                            59.00 39.77      32.27     32.04                                 12   135.17                                                                            125.10                                                                            58.99 39.78      32.28     32.05                                 13   135.16                                                                            125.08                                                                            58.99 39.78      32.27     32.05                                 14   135.17                                                                            125.09                                                                            59.00 39.77      32.27     32.04                                 15   135.15                                                                            125.12                                                                            58.99 39.78      32.29     32.05                                 16   135.15                                                                            125.11                                                                            58.98 39.77      32.28     32.05                                 17   135.15                                                                            125.12                                                                            59.00 39.77      32.29     32.05                                 18   135.16                                                                            125.10                                                                            58.98 39.77      32.29     32.05                                 19   135.15                                                                            125.10                                                                            58.98 39.78      32.28     32.05                                 __________________________________________________________________________             .sup.13 C-NMR δ(ppm)                                            units)prenecis-iso-(number of n                                                        ##STR44##                                                                              ##STR45##                                                                              ##STR46##                                                                             ##STR47##                                                                             ##STR48##                         __________________________________________________________________________    11       26.47    23.42    25.67   17.64   15.98                              12       26.47    23.42    25.66   17.64   15.98                              13       26.48    23.42    25.67   17.65   15.99                              14       26.47    23.42    25.66   17.64   15.97                              15       26.49    23.42    25.65   17.65   15.99                              16       26.49    23.42    25.65   17.64   15.98                              17       26.49    23.41    25.66   17.65   15.99                              18       26.48    23.41    25.64   17.64   15.99                              19       26.49    23.42    25.65   17.65   15.98                              __________________________________________________________________________

EXAMPLE 2

Ten kilograms (in the undried state) of the nonyellowed leaves of Ginkobiloba, which were collected in Kurashiki City, Japan at the end ofOctober, were dried with hot air at about 40° C. for 24 hours, and thenextracted with 80 liters of chloroform at about 15° C. The chloroformwas removed from the extract and 5 liters of petroleum ether was addedto the concentrate. The insoluble components were separated byfiltration. The filtrate was concentrated and chromatographed on asilica gel column using chloroform as an eluent to separate a fractionhaving an Rf value of 0.50 and 0.19 determined by the same thin-layerchromatography as described in Example 1. Thus, about 37 g of an oilyproduct was obtained. About 400 ml of acetone was added to the oilyproduct to dissolve acetone-soluble components. The resulting residuewas filtered, and the filtrate was concentrated. The oily productobtained was heated at 65° C. for 2 hours together with 400 ml ofmethanol, 40 ml of water and 20 g of sodium hydroxide. Methanol was thendistilled off and diethyl ether (500 ml) was added to the resultingproduct to perform extraction. The ethereal layer was washed with about100 ml of water five times, and dried over anhydrous sodium sulfate. Thesolvent was distilled off to give 24.2 g of an oily product.

The oily product was then chromatographed on a column of about 1 kg ofsilica gel using a mixture of n-hexane/isopropyl ether (90/10 by volume)as an eluent to separate a fraction having an Rf value of 0.19determined by the same thin-layer chromatography as described inExample 1. Thus, 21.8 g of an oily product was obtained. The oilyproduct was a polyprenol fraction having a purity of more than 95%. Thedistribution of the molecular weight of the polyprenol fraction measuredin the same way as in Example 1 is shown in Table 5.

EXAMPLE 3

Five kilograms (in the undried state) of the leaves of Ginkgo bilobacollected in Kurashiki City, Japan at the middle of June were treated inthe same way as in Example 1 except that the saponification reactionwith sodium hydroxide was not carried out. There was obtained 8.7 g ofan oily product. The oily product was polyprenyl acetate having a purityof more than 90%. The product was analyzed by the same high-performanceliquid chromatography as in Example 1 (except that the developingsolvent was changed to a mixed solvent of acetone/methanol in a volumeratio of 70/30), and the area proportions of the individual peaks weredetermined, and are shown in Table 5.

Furthermore, the individual components of the oily product wereseparated by using the same high-performance liquid chromatographiccolumn for semipreparative chromatography as used in Example 1 (exceptthat the developing solvent was changed to a mixture of acetone/methanolin a volume ratio of 70/30), and analyzed by FD-MASS, IR, ¹ H-NMR and ¹³C-NMR. As a result, these components were determined to be thepolyprenyl acetates represented by general formula (I). The areaproportions of the individual peaks in the high-performance liquidchromatogram are shown in Table 5, and the FD-MASS analysis values ofthese components are tabulated below.

    ______________________________________                                        Peak                  ED-MASS (m/e)                                           Number    n           Found   Calculated                                      ______________________________________                                        1         11          1012    1012                                            2         12          1080    1080                                            3         13          1148    1148                                            4         14          1216    1216                                            5         15          1284    1284                                            6         16          1352    1352                                            7         17          1420    1420                                            8         18          1488    1488                                            9         19          1556    1556                                            ______________________________________                                    

EXAMPLE 4

Leaves of Ginko biloba collected in Kurashiki City, Japan at the end ofOctober were dried with hot air at about 60° C. for 65 hours, and thendivided into 100 g-portions. Each of these portions was dipped in 1liter of each of the solvents shown in Table 4 to extract the ginkgoleaves at about 25° C. for 7 days. The solvent was distilled off fromthe extract, and the weight of the resulting concentrate was measured.The measured weight is shown in Table 4 as the total amount of theextract.

Each of these concentrates was dissolved in 200 ml of hexane, and thesolution was washed with about 100 ml of a mixture of methanol and waterin a volume ratio of 9:1 three times, and dried over anhydrous magnesiumsulfate. The solvent was distilled off to give an oily product.

The oily product was heated at 65° C. for 2 hours together with 50 ml ofmethanol and 1 g of potassium hydroxide. The methanol was then distilledoff, and 100 ml of diethyl ether was added to the residue to extract it.The ethereal layer was washed with about 50 ml of a saturated aqueoussolution of sodium chloride three times, and dried over anhydrousmagnesium sulfate. The solvent was distilled off to give an oilyproduct. The oily product was separated by using 100 g of silica gel anda mixture of hexane and ethyl acetate in a volume ratio of 9:1 to obtaina polyprenol mixture. The weight of the polyprenol mixture is shown inTable 4 as the polyprenol content.

The composition of the resulting polyprenol mixtures was substantiallythe same as that of the polyprenol mixture obtained in Example 2irrespective of the type of the solvents used.

                  TABLE 4                                                         ______________________________________                                                         Total amount                                                                  of the extract                                                                           Polyprenol                                        Solvent          (g)        content (g)                                       ______________________________________                                        n-Hexane         4.65       0.92                                              Petroleum ether  4.60       1.06                                              Benzene          6.18       1.03                                              Chloroform       7.82       0.98                                              Carbon tetrachloride                                                                           5.83       0.89                                              Diethyl ether    6.85       1.14                                              Tetrahydrofuran  10.51      0.97                                              Methanol         33.72      0.30                                              Ethanol          21.71      0.69                                              Isopropyl alcohol                                                                              5.88       0.82                                              Acetone          8.49       1.14                                              Ethyl acetate    7.24       1.13                                              Acetone/hexane (20/80)                                                                         6.34       1.16                                              Acetone/hexane (50/50)                                                                         8.68       1.34                                              Acetone/chloroform (20/80)                                                                     8.32       1.14                                              Acetone/chloroform (50/50)                                                                     8.09       1.18                                              Methanol/chloroform (20/80)                                                                    14.60      1.10                                              Methanol/chloroform (50/50)                                                                    22.88      1.00                                              Diethylether/hexane (20/80)                                                                    5.34       1.01                                              Methanol/acetone (20/80)                                                                       17.28      1.05                                              Methanol/acetone (50/50)                                                                       28.30      0.90                                              ______________________________________                                    

EXAMPLE 5

Ten kilograms of the leaves of Cedrus deodara collected in KurashikiCity, Japan at the end of May were worked up by the same operation asshown in Example 2 to give 22.1 g of an oily product. The molecularweight distribution of the oily product measured by the same method asshown in Example 1 is shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                   Example                                                            Peak No.   n     1         2     3       5                                    ______________________________________                                        1          11    1.8       0.3   1.2     0.76                                 2          12    3.1       1.1   4.5     2.06                                 3          13    9.4       5.9   14.4    7.00                                 4          14    31.1      25.0  28.1    24.32                                5          15    35.2      39.4  33.4    38.54                                6          16    12.7      19.2  13.0    19.22                                7          17    3.8       5.9   3.8     5.19                                 8          18    1.7       1.8   1.2     1.39                                 9          19    1.2       0.8   0.4     0.54                                 Average of n     14.6      15.0  14.5    14.8                                 Total of         79.0%     84.2% 75.0%   82.1%                                n = 14, 15, 16                                                                ______________________________________                                    

EXAMPLE 6

Synthesis of polyprenyl acetate:

1.24 g of polyprenol of general formula (III) in which n is 15 and X is--OH and 1.0 g of pyridine were dissolved in dry diethyl ether, and 1.2g of acetic anhydride was added dropwise to the solution at roomtemperature. After the addition, the mixture was stirred overnight atroom temperature. The reaction mixture was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous magnesiumsulfate. The diethyl ether was distilled off to give a pale yellowviscous liquid. The product was purified by silica gel columnchromatography using hexane/ethyl acetate as an eluent to give 1.08 g ofa slightly yellow liquid. IR analysis of this liquid showed that theabsorption at about 3,300 cm⁻¹ attributed to the OH group of thestarting polyprenol disappeared, and absorptions at 1745 cm⁻¹ and 1255cm⁻¹ attributed to --OCOCH₃ newly appeared. In NMR analysis, the signal(doublet. δ=4.08) assigned to --CH₂ OH of the starting polyprenoldisappeared, and a new signal (doublet, δ=4.55) assigned to --CH₂ OCOCH₃was observed. The signal to be assigned to --CH₂ OCOCH₃ was seen tooverlap the signal (δ=2.04) assigned to ##STR49## FD-MASS analysis gavem/e=1284. From these data, the resulting liquid was determined to bepolyprenyl acetate of general formula (III) in which n is 15 and X is--OCOCH₃.

A polyprenyl acetate in which n is other than 15, and a polyprenylacetate mixture in which n distributes arbitrarily between 11 and 19were synthesized by a similar operation to that described above.

EXAMPLE 7

Synthesis of polyprenyl bromide:

12.4 g of polyprenol of general formula (III) in which n is 15 and X is--OH and 1 ml of pyridine were added to 200 ml of n-hexane. To theresulting solution was added dropwise 2.0 g of phosphorus tribromideunder an atmosphere of nitrogen. After the addition, the mixture wasstirred overnight at room temperature under an atmosphere of nitrogen.The n-hexane solution was put in a separating funnel, washed with about50 ml of water ten-times, and then dried over anhydrous magnesiumsulfate. The n-hexane was distilled off to give 12.0 g of a slightlyyellow liquid product. When this product was analyzed by NMRspectroscopy, the signal (doublet, δ=4.08) assigned to the --CH₂ OHgroup of the starting polyprenol disappeared, and a signal (doublet,δ=3.91) assigned to --CH₂ Br appeared newly. FD-MASS analysis of thisliquid product gave m/e=1304. From these analytical data, the aboveproduct was determined to be polyprenyl bromide of general formula (II)in which n is 15 and A.sub. 2 is Br.

By a similar operation to that described above, a polyprenyl bromide inwhich n is other than 15, and a polyprenyl bromide mixture in which ndistributes arbitrarily between 11 and 19 synthesized.

0.66 g of the above polyprenyl bromide (n=15) was dissolved in 10 ml ofdimethyl formamide, and 1.0 g of anhydrous sodium acetate was added. Themixture was stirred overnight at about 50° C. Then, about 50 ml ofdiethyl ether was added, and the mixture was filtered. The filtrate waswashed with about 20 ml of water ten times, and dried over anhydrousmagnesium sulfate. The solvent was distilled off to give 0.58 g of apale yellow liquid product. The product was identical in NMR spectrumdata and m/e values in FD-MASS analysis with the polyprenyl acetate(n=15) obtained in Example 6, and was therefore determined to bepolyprenyl acetate of formula (III) in which n is 15 and X is --OCOCH₃.

EXAMPLE 8

Synthesis of polyprenyl chloride:

12.4 g of polyprenol of general formula (III) in which n is 15 and X is--OH and 1.0 ml of pyridine were added to 200 ml of n-hexane. To theresulting solution was added dropwise 1.5 g of thionyl chloride at roomtemperature under an atmosphere of nitrogen. After the addition, themixture was further stirred at room temperature for 2 hours. Thereaction mixture was then worked up in the same way as in Example 7 togive 11.2 g of a pale yellow liquid. IR analysis of the resulting liquidshowed that the absorption attributed to the --OH group of the startingpolyprenol disappeared. NMR analysis showed that the signal assigned to--CH₂ OH of the starting polyprenol disappeared, and a signal (doublet,δ=3.95) assigned to --CH₂ Cl newly appeared. The FD-MASS analysis gavem/e=1260. From these analytical data, the above product was determinedto be polyprenyl chloride of general formula (II) in which n is 15 andA₂ is Cl.

By a similar operation to that described above, a polyprenyl chloride inwhich n is other than 15 and a polyprenyl chloride mixture in which ndistributes arbitrarily between 11 and 19 were synthesized.

EXAMPLE 9

Synthesis of polyprenyl formate:

0.8 ml of acetic anhydride and 2 ml of 99% formic acid were mixed underice cooling, and the mixture was stirred at room temperature for 2hours. To the resulting mixture was added 1.24 g of polyprenol ofgeneral formula (III) in which n is 15 and X is --OH. The mixture wasstirred under ice cooling for one hour. The resulting reaction mixturewas poured into water, and stirred for 30 minutes. It was then extractedwith diethyl ether. The ethereal layer was well washed with water andthen with a saturated aqueous solution of sodium chloride, and thendried over anhydrous magnesium sulfate. The ether was distilled off togive 0.48 g of a yellow liquid. This liquid was very unstable. The IRanalysis of this product showed that the absorption attributed to the OHgroup of the starting polyprenol disappeared, and an absorptionattributed to the --OCOH group appeared at 1725 cm⁻¹ and 1160 cm⁻¹. Inthe NMR analysis of the product, a signal (singlet, δ=7.90) assigned tothe --OCOH group was observed. From these analytical data, the productwas determined to be a compound of formula (II) in which n is 15 and A₂is -- OCOH.

A polyprenyl formate in which n is other than 15 and a polyprenylformate mixture in which n distributes arbitrarily between 11 and 19were synthesized by a similar operation to that described above.

EXAMPLE 10

Synthesis of polyprenyl trifluoroacetate:

1.24 g of polyprenol of general formula (III) in which n is 15 and X is--OH and 1.0 g of pyridine were dissolved in 10 ml of methylenechloride, and 0.5 g of trifluoroacetic anhydride was added dropwise at0° to 5° C. The mixture was stirred at room temperature for 30 minutes.The reaction mixture was poured into water and extracted with diethylether. The ethereal layer was washed successively with dilutehydrochloric acid, water and a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off to give 0.83 g of a yellow liquid. The IR analysis of thisliquid showed that the absorption attributed to the OH group of thestarting polyprenol disappeared, and an absorption attributed totrifluoroacetate appeared newly at 1790 cm⁻¹, 1210 cm⁻¹ and about 1140cm⁻¹. In the NMR analysis, the signal assigned to --CH₂ OH of thestarting polyprenol disappeared, and a new signal (doublet, δ=4.72)assigned to --CH₂ OCOCF₃ was observed. The FD-MASS analysis gavem/e=1338. From these analytical data, this product was determined to bea compound of general formula (II) in which n is 15 and A₂ is OCOCF₃.

A polyprenyl trifluoroacetate in which n is other than 15 and apolyprenyl trifluoroacetate mixture in which n distributes arbitrarilybetween 11 and 19 were synthesized by a similar operation to thatdescribed above.

EXAMPLE 11

Synthesis of polyprenyl monochloroacetate:

1.24 g of polyprenol of general formula (III) in which n is 15 and X isOH and 1.0 g of pyridine were dissolved in 10 ml of methylene chloride,and 0.4 g of monochloroacetic anhydride was added dropwise to 0° to 5°C. The mixture was stirred overnight at room temperature. Then, thereaction mixture was worked up in the same way as in Example 10 to give1.30 g of a pale yellow liquid. The liquid product was further purifiedby silica gel column chromatography using hexane/ethyl acetate as aneluent to give 1.25 g of a liquid. The IR analysis of the resultingliquid showed that the absorption attributed to the OH group of thestarting polyprenol disappeared, and an absorption attributed to C═Oappeared at about 1750 cm⁻¹. In the NMR spectrum, the signal assigned to--CH₂ OH disappeared, and a signal (doublet, δ=4.57) assigned to --CH₂OCOCH₂ Cl and a signal (singlet, δ=3.92) assigned to --OCOCH₂ Cl newlyappeared. The FD-MASS analysis gave m/e=1318. From these analyticaldata, the liquid product was determined to be a compound of generalformula (II) in which n is 15 and A₂ is --OCOCH₂ Cl.

A polyprenyl monochloroacetate in which n is other than 15, and apolyprenyl monochloroacetate mixture in which n distributes arbitrarilybetween 11 and 19 were synthesized by a similar operation to thatdescribed above.

EXAMPLE 12

Synthesis of polyprenyl propionate:

The same operation as in Example 6 was repeated except that 1.53 g ofpropionic anhydride was used instead of the acetic anhydride. There wasobtained 1.02 g of a slightly yellow liquid. The IR analysis of theliquid showed that the absorption attributed to the --OH group of thestarting polyprenol disappeared, and an absorption attributed to --OCOC₂H₅ appeared at 1740 cm⁻¹ and 1250 cm⁻¹. In the NMR sprectrum, the signalassigned to --CH₂ OH of the starting polyprenol disappeared, and asignal (doublet, δ=4.56) assigned to --CH₂ OCOC₂ H₅ was observed. TheFD-MASS analysis gave m/e=1298. From these analytical data, the liquidwas determined to be a compound of general formula (II) in which n is 15and A₂ is --OCOC₂ H₅.

A polyprenyl propionate in which n is other than 15, and a polyprenylpropionate mixture in which n distributes arbitrarily between 11 and 19were synthesized by a similar operation to that described above.

EXAMPLE 13

Synthesis of polyprenyl oleate:

(1) 1.24 g of polyprenol of general formula (III) in which n is 15 and Xis --OH, 0.5 g of methyl oleate and 0.01 g of sodium hydride weredissolved in 50 ml of toluene, and the solution was heated at 110° C.for 24 hours under an atmosphere of nitrogen. The reaction solution wascooled at room temperature, washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. The solventwas distilled off to give a yellow liquid. The liquid was purified bysilica gel column chromatography using hexane/ethyl acetate as an eluentto give 0.48 g of a colorless viscous liquid. The IR analysis of theliquid showed that the absorption attributed to the OH group of thestarting polyprenol disappeared. The FD-MASS analysis gave m/e=1506.From these analytical data, the liquid was determined to be a compoundof general formula (II) in which n is 15 and A₂ is --OCO--CH₂ --₇CH═CH--CH₂)₇ CH₃.

(2) 1.17 g of a polyprenol of general formula (III) in which n is 14 andX is --OH, 0.3 g of methyl oleate and 0.05 g of potassium hydroxide weredissolved in 50 ml of toluene, and the solution was heated at 110° C.for 8 hours under an atmosphere of nitrogen. After the reaction, thereaction mixture was cooled at room temperature, washed with water anddried. The solvent was distilled off to give 1.2 g of a pale yellowliquid. By the same analyses as above, this product was determined to bea compound of formula (II) in which n is 14 and A₂ is --OCO--CH₂)₇CH═CH--CH₂)₇ CH₃.

EXAMPLE 14

Syntheses of polyprenyl stearate:

Polyprenol of general formula (III) in which n is 15 and X is OH andmethyl stearate were subjected to esterexchange reaction in the same wayas in Example 13-(2) except that 0.3 g of methyl stearate was usedinstead of 0.3 g of methyl oleate. There was obtained 1.2 g of a paleyellow liquid. FD-MASS analysis gave m/e=1508 which showed that thisproduct was a polyprenyl compound of general formula (II) in which n is15 and A₂ is --OCO--(CH₂)₁₆ CH₃.

EXAMPLE 15

Synthesis of polyprenyl benzoate:

Benzoyl chloride (0.28 g) was added to a mixture of 1.24 g of polyprenolof general formula (III) in which n is 15 and X is --OH and 10 ml ofpyridine at room temperature, and the mixture was stirred overnight atroom temperature. The reaction mixture was poured into about 150 ml ofwater, and extracted with diethyl ether. The ethereal layer was washedwith a saturated aqueous solution of sodium chloride, dilutehydrochloric acid, water, an aqueous solution of sodium bicarbonate andagain a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The ether was distilled off to give ayellow liquid. The yellow liquid was purified by silica gel columnchromatography using hexane/ethyl acetate as an eluent to give 0.92 g ofa slightly yellow liquid. The IR spectrum of the resulting liquid showedthat the absorption attributed to the OH group of the startingpolyprenol disappeared, and an absorption attributed to the esterlinkage appeared at 1715 cm⁻¹ and 1270 cm⁻¹. The FD-MASS analysis gavem/e=1346. From these analytical data, this product was determined to bea compound of general formula (II) in which n is 15 and A₂ is --OCOC₆H₅.

By a similar operation to that described above, a polyprenyl benzoate inwhich n is other than 15 and a polyprenyl benzoate mixture in which ndistributes arbitrarily between 11 and 19 were synthesized.

EXAMPLE 16-1

Synthesis of polyprenyl methyl ether:

1.24 g of polyprenol of general formula (III) in which n is 15 and X is--OH was dissolved in 10 ml of a 1:1 mixture of anhydrous diethyl etherand hexane, and 0.69 ml (1.1 millimoles) of a 1.6M hexane solution ofn-butyllithium was added dropwise at 0° C. The mixture was stirred for10 minutes, and then 156 mg (1.1 millimoles) of methyl iodide was added.After additional stirring for 30 minutes, the reaction mixture waspoured into water, and extracted with hexane. The hexane layer waswashed with a saturated aqueous solution of sodium chloride and driedover anhydrous magnesium sulfate. The solvent was distilled off to givea yellow liquid. The liquid was purified by silica gel columnchromatography using hexane/ethyl acetate as an eluent to give 1.14 g ofa slightly yellow liquid. The IR analysis of the purified liquid showedthat the absorption attributed to the OH group of the startingpolyprenol disappeared, and an absorption attributed to the etherlinkage appeared at 1120 cm⁻¹, 1100 cm⁻¹ and 1080 cm⁻¹. In the NMRspectrum, a signal assigned to --OCH₃ appeared at δ=3.27. The FD-MASSanalysis gave m/e=1256. From these analytical data, the liquid productwas determined to be a compound of general formula in which n is 15 andA₂ is --OCH₃.

By a similar operation to that described above, a polyprenyl methylether in whch n is other than 15 and a polyprenyl methyl ether mixturein which n distributes arbitrarily between 11 and 19 were synthesized.

EXAMPLE 16-2

Synthesis of polyprenyl phenyl ether:

168 mg of finely divided potassium hydroxide and 310 mg of phenol weredissolved in 30 ml of dimethoxyethane warmed to about 60° C., and 1.30 gof polyprenyl bromide of general formula (II) in which n is 15 and A₂ isBr was added. The mixture was heated under reflux for 6 hours. Thereaction mixture was cooled, poured into water, and extracted withdiethyl ether. The ethereal layer was washed with a 5% aqueous solutionof sodium hydroxide twice and then with a saturated aqueous solution ofsodium chloride, and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off to give a yellow liquid. The liquid waspurified by silica gel column chromatography using hexane as an eluentto give 0.42 g of a slightly yellow liquid. The IR analysis of theresulting liquid showed that an absorption attributed to phenyl etherappeared at 1600 cm⁻¹, 1580 cm⁻¹ and 1220 cm⁻¹. In the NMR spectrum, thesignal (doublet, δ =3.91) assigned to --CH₂ Br of the startingpolyprenyl bromide disappeared, and a signal (doublet, δ=4.39) assignedto --CH₂ --O--C₆ H₅ newly appeared. The FD-MASS analysis gave m/e=1318.From these analytical data, the liquid was determined to be a compoundof formula (II) in which n is 15 and A₂ is --OC₆ H₅.

By a similar operation to that described above, a polyprenyl phenylether in which n is other than 15 and a polyprenyl phenyl ether mixturein which n distributes arbitrarily between 11 and 19 were synthesized.

EXAMPLE 17

Synthesis of polyprenyl 2-pyridyl ether:

0.5 g of 50% sodium hydride was added to 25 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Asolution of 12.4 g of polyprenol in which n is 15 and X is OH in 10 mlof anhydrous N,N-dimethylformamide was added dropwise. After theaddition, the mixture was stirred for 1 hour. Then, 1.1 ml of2-chloropyridine was added, and the mixture was stirred overnight atroom temperature. The reaction mixture was poured into about 100 ml ofwater, and extractd with diethyl ether. The ethereal layer was washedwith water, dried and then concentrated to give a yellow liquid product.the liquid product was chromatographed on a silica gel column usinghexane/ethyl acetate as an eluent to give 9.9 g of a slightly yellowliquid. The NMR analysis of the liquid showed that the signal (doublet,δ=4.08) assigned to --CH₂ OH of the starting polyprenol disappeared, anda signal (doublet, δ=4.71) assigned to --CH₂ H-- and a signal(multiplet, δ=6.50-6.72, multiplet δ= 7.30-7.52, multiplet δ=8.00-8.08)assigned to ##STR50## newly appeared. The FD-MASS analysis gavem/e=1319. From these analytical data, this liquid was dtermined to bepolyprenyl 2-pyridyl ether of general formula (II) in which n is 15 andA₂ is a 2)pyridyloxy group.

By a similar operation to that described above, a polyprenyl-2-pyridylether in which n is other than 15, and a polyprenyl-2-pyridyl ethermixture in which n distributes arbitrarily between 11 and 19 weresynthesized.

EXAMPLE 18

Synthesis of polyprenyl 2-benzothiazolyl ether:

528 mg of 50% sodium hydride was washed with dry hexane several timesunder an atmosphere of nitrogen, and 50 ml of anhydrous tetrahydrofuranand 50 ml of anhydrous dimethyl formamide were added. The mixture wasstirred. Then, 12.4 g of polyprenol of general formula (III) in which nis 15 and X is --OH was added, and the mixture was stirred at 10° C. for1 hour. 1.3 ml of 2-chlorobenzothiazole was added dropwise. After theaddition, the mixture was stirred at 10° C. for 2 hours and then at roomtemperature overnight, and threafter poured into about 200 ml of water.It was extracted with diethyl ether, and the extract was washed withwater, dried and concentrated to give 12.5 g of a yellow liquid. Inthin-layer chromatography, this compound showed a single spot. The yieldof the product was almost quantitative, and no further purification wasrequired. When this liquid was subjected to silica gel columnchromatography, it was partially decomposed. The NMR analysis of theliquid showed that the signal (doublet, δ=4.08) assigned to --CH₂ OH ofthe starting polyprenol disappeared, and a signal (doublet, δ=5.96)assigned to --CH₂ H-- and a signal (multiplet, δ=6.97-7.62) assigned toaromatic protons of ##STR51## appeared newly. The FD-MASS analysis ofthis liquid gave m/e=1375.

From the above analytical data, this liquid product was determined to bepolyprenyl 2-benzothiazolyl ether of general formula (II) in which n is15 and A₂ is ##STR52##

By a similar operation to that described above, a polyprenyl2-benzothiazolyl ether in which n is other than 15 and a polyprenyl2-benzothiazolyl ether mixture in which n distributes arbitrarilybetween 11 and 19 were synthesized.

EXAMPLE 19

Synthesis of polyprenyl t-butyldimethylsilyl ether:

1.24 g of polyprenol of general formula (III) in which n is 15 and X is--OH was dissolved in 10 ml of methylene chloride, and 202 mg oftriethylamine, 151 mg of t-butyldimethylsilyl chloride and 5 mg of4-dimethylaminopyridine were added. The mixture was stirred overnight atroom temperature. The reaction mixture was poured into water, andextracted with diethyl ether. The ethereal layer was washed with waterand a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The solvent was distilled off to give aliquid. The liquid was purified by column chromatography on a column ofsilica gel CC-7 (a product of Mallinckrodt) using hexane as an eluent togive 1.30 g of a liquid. The IR analysis of the purified liquid showedthat the absorption attributed to the OH group of the startingpolyprenol at about 3300 cm⁻¹ disappeared. In the NMR spectrum, a signal(singlet, δ=0.85) assigned to --OSiMe₂ t-Bu was observed. The FD-MASSanalysis gave m/e=1356.

From the above analytical data, this liquid was determined to bepolyprenyl t-butyldimethylsilyl ether of general formula (II) in which nis 15 and A₂ is --OSiMe₂ t-Bu.

By a similar operation to that described above, a polyprenylt-butyldimethylsilyl ether in which n is other than 15 and a polyprenylt-butyldimethylsilyl ether mixture in which n distributes arbitrarilybetween 11 and 19 were synthesized.

EXAMPLE 20

Synthesis of polyprenyl methyl sulfide:

1.30 g of polyprenyl bromide of general formula (II) in which n is 15and A₂ is Br was dissolved in 1.5 ml of benzene, and 3 ml of a 15%aqueous solution of methylmercaptan sodium salt and 50 mg of benzyltriethyl ammonium chloride were added. The mixture was stirredvigorously overnight at 40° C. The reaction mixture was cooled, andextracted with diethyl ether. The ethereal layer was washed with waterand a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The ether was distilled off to give ayellow liquid. The liquid was purified by silica gel columnchromatography using hexane as an eluent to give 0.40 g of a liquid. TheNMR analysis of this liquid showed that a signal (singlet, δ=1.95)assigned to S--CH₃ and a signal (doublet, δ=2.96) assigned to --CH₂ SCH₃appeared. The FD-MASS analysis gave m/e=1272. From these analyticaldata, this liquid was determined to be a compound of general formula(II) in which n is 15 and A₂ is SCH₃.

By a similar operation to that described above, a polyprenyl methylsulfide in which n is other than 15 and a polyprenyl methyl sulfidemixture in which n distributes arbitrarily between 11 and 19 weresynthesized.

EXAMPLE 21

Synthesis of polyprenyl phenyl sulfide:

2.2 g of thiophenol and 2.8 g of potassium carbonate were added to 50 mlof N,N-dimethylformamide, and with stirring at about 20° C., 13.0 g ofpolyprenylbromide of general formula (II) in which n is 15 and A₂ is Brwas added dropwise. After the addition, the mixture was stirredovernight at room temperature. The reaction mixture ws poured into about100 ml of water and extracted with hexane. The hexane layer was washedwith a 10% aqueous solution of sodium hydroxide and water, and thendried over anhydrous magnesium sulfate. The hexane was distilled off togive a yellow liquid. The yellow liquid was purified by silica gelcolumn chromatography using methylene chloride as an eluent to give 8.6g of a slghtly yellow liquid. The NMR analysis of this liquid showedthat a signal (doublet, δ=3.91) assigned to --CH₂ Br of the startingpolyprenyl bromide disappeared, and a signal (doublet, δ=3.47) assignedto --CH₂ S-- and a signal (multiplet, δ= 7.05-7.32) assigned to --SC₆ H₅newley appeared. The FD-MASS analysis gave m/e=1334.

From these analytical data, the liquid product was determined to bepolyprenyl phenyl sulfide of general formula (II) in which n is 15 andA₂ is --SC₆ H₅.

By a similar operation to that described above, a polyprenyl phenylsulfide mixture in which n distributes arbitrarily between 11 and 19were synthesized.

EXAMPLE 22

Synthesis of polyprenyl 2-thiazolinyl sulfide:

1.35 g of 2-mercaptothiazoline and 0.48 g of 50% sodium hydride wereadded to 15 ml of N,N-dimethylformamide, and the mixture was stirred atroom temperature for 1 hour. A solution of 6.5 g of polyprenyl bromideof general formula (II) in which n is 15 and A₂ is Br in 5 ml ofN,N-dimethylformamide was added dropwise. After the addition, themixture was stirred overnight at room temperature. The reaction mixturewas poured into about 50 ml of water, and extracted with diethyl ether.The extract was washed with water, dried and concentrated to give ayellow liquid. The liquid was purified by silica gel columnchromatography using hexane/ethyl acetate as an eluent to give 2.8 g ofa slightly yellow liquid. The NMR analysis of this liquid showed that asignal (doublet, δ=3.91) assigned to --CH₂ Br of the starting polyprenylbromide disappeared, and a signal (doublet, δ=3.74) assigned to --CH₂ Sand signals (triplet, δ=3.32, and triplet, δ=4.16) assigned to ##STR53##newly appeared. The FD-MASS analysis of this liquid gave m/e=1343. Fromthe above analytical data, this liquid was determined to be polyprenyl2-thiazolinyl sulfide of general formula (II) in which n is 15 and A₂ is##STR54##

By a similar operation to that described above, a polyprenyl2-thiazolinyl sulfide in which n is other than 15 and a polyprenyl2-thiazolinyl sulfide mixture were synthesized.

EXAMPLE 23

Synthesis of polyprenyl 2-pyridyl sulfide:

1.11 g of 2-mercaptopyridine and 0.48 of 50% sodium hydride weredissolved in 25 ml of dimethyl formamide, and the mixture was stirred atroom temperature for 1 hour. A solution of 6.5 g of polyprenyl bromideof general formula (II) in which n is 15 and A₂ is Br in 5 ml ofN,N-dimethylformamide was added dropwise. After the addition, themixture was stirred overnight at room temperature. The reaction mixturewas poured into about 50 ml of water, and extracted with diethyl ether.Then, the diethyl ether layer was washed with water and dried overanhydrous magnesium sulfate. The ether was distilled off to give ayellow liquid. The liquid was purified by silica gel columnchromatography using hexane/ethyl acetate as an eluent to give 3.9 g ofa slightly yellow liquid. The NMR analysis of this liquid showed thatthe signal (doublet, δ=3.91) assigned to --CH₂ Br of the startingpolyprenyl bromide disappeared, and a signal (doublet, δ=3.78) assignedto --CH₂ S and a signal (multiplet, δ=6.75-8.35) assigned to --S--C₅ H₄N newly appeared. The FD-MASS analysis of this liquid gave m/e=1335.

From the above analytical data, this liquid was determined to bepolyprenyl 2-pyridyl sulfide of general formula (II) in which n is 15and A₂ is --SC₅ H₄ N.

By a similar operation to that described above, a polyprenyl 2-pyridylsulfide in which n is other than 15 and a polyprenyl 2-pyridyl sulfidemixture in which n distributes arbitrarily between 11 and 19 weresynthesized.

EXAMPLE 24

Synthesis of polyprenyl diethyl phosphate:

1.24 g of polyprenol of formula (III) in which n is 15 and X is --OH and0.16 ml of pyridine were dissolved in 5 ml of methylene chloride, and asolution of 181 mg of diethyl phosphorochloridate in 2 ml of methylenechloride was added dropwise at 0° C. under an atmosphere of nitrogen.The mixture was stirred at 0° C. for 1 hour and then overnight at roomtemperature. Water was added to the reaction mixture, and it wasextracted with diethyl ether. The ethereal layer was washed successivelywith dilute hydrochloric acid, water, a saturated aqueous solution ofsodium bicarbonate, and a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The ether was distilled offto give 1.35 g of a pale yellow liquid. This liquid showed a single spotin thin-layer chromatography, and no side-reaction was observed. Theyield was almost quantitative, and no further purification was required.The IR analysis of this liquid showed that an absorption at 1260 cm⁻¹attributed to P═0 and a broad absorption at 1050 to 940 cm⁻¹ attributedto P--O--C alkyl appeared. In the NMR spectrum, a signal (doubledoublet, δ=4.38) assigned to ##STR55## and signals (multipletδ=3.8-4.15, and triplet, δ=1.28) assigned to ##STR56## appeared. TheFD-MASS analysis gave m/e=1378.

From these analytical data, the liquid was determined to be a compoundof general formula (II) in wich n is 15 and A₂ is OP(O)(OEt)₂.

By a similar operation to that described above, a polyprenyl diethylphosphate in which n is other than 15, and a polyprenyl diethylphosphate mixture in which n distributes arbitrarily between 11 and 19were synthesized.

EXAMPLE 25

Synthesis of polyprenyl phenyl sulfoxide:

1.33 g of polyprenyl phenyl sulfide of general formula (II) in which nis 15 and A₂ is SC₆ H₅ was dissolved in 10 ml of methanol, and asolution of 257 mg of sodium metaperiodate in 5 ml of water was added.The mixture was stirred overnight at room temperature. An aqueoussolution of sodium chloride was added to the reaction mixture, and itwas extracted with diethyl ether. The ethereal layer was washed withwater and a saturated aqueous solution of sodium chloride, and driedover anhydrous magnesium sulfate. The ether was distilled off to give ayellow liquid. The liquid was purified by silica gel columnchromatography using hexane/ether as an eluent to give 1.06 g of apurified liquid. The IR analysis of this purified liquid showed that astrong absorption at 1035 cm⁻¹ attributed to sulfoxide which did notexist in the starting polyprenyl phenyl sulfide appeared. In the NMRspectrum, a signal (doublet, δ=3.47) assigned to --CH₂ SC₆ H₅ of thestarting polyprenyl phenyl sulfide disappeared, and a signal (doublet,δ=3.35) assigned to --CH₂ SOC₆ H₅ appeared. The FD-MASS analysis gavem/e=1350. From the above analytical data, this liquid was identified tobe polyprenyl phenyl sulfoxide of general formula (II) in which n is 15and A₂ is --SOC₆ H₅.

By a similar operation to that described above, a polyprenylphenylsulfoxide in which n is other than 15 and a polyprenyl phenyl sulfoxidemixture in which n distributes arbitrarily between 11 and 19 weresynthesized.

EXAMPLE 26

Synthesis of polyprenyl phenyl sulfone:

1.30 g of polyprenyl bromide of general formula (II) in which n is 15and A₂ is Br was dissolved in a mixtue of 10 ml of N,N-dimethylformamideand 10 ml of tetrahydrofuran, and 0.33 g of sodium phenylsulfinate wasadded. The mixture was stirred at room temperature for 17 hours and thenat 50° C. for 1 hour. The solvent was removed by a rotary evaporator,and water was added to the reaction mixture, followed by extraction withbenzene. The benzene layer was washed with water and dried overanhydrous magnesium sulfate. Removal of the solvent gave a yellowliquid. The liquid was purified by silica gel column chromatographyusing hexane/ethyl acetate as an eluent to give 0.94 g of a pale yellowliquid. The ¹ H-NMR analysis of this liquid showed that the signal(doublet, δ=3.91) assigned to --CH₂ Br of the starting polyprenylbromide disappeared, and a signal (doublet, δ=3.77) assigned to --CH₂SO₂ C₆ H₅ and a signal (multiplet, δ=7.31-7.93) assigned to --SO₂ C₆ H₅newly appeared. The FD-MASS analysis of the liquid gave m/e=1366. Fromthese analytical data, this liquid was determined to be a compund ofgeneral formula (II) in which n is 15 and A₂ is --SO₂ C₆ H₅.

By a similar operation to that described above, a polyprenyl phenylsulfone in which n is other than 15 and a polyprenyl phenyl sulfonemixture in which n distributes arbitrarily between 11 and 19 weresynthesized.

EXAMPLE 27

Synthesis of polyprenyl ethyl carbonate:

12.4 g of polyprenol of general formula (III) in which n is 15 and X is--OH was dissolved in 50 ml of anhydrous pyridine, and with stirring atroom temperature, 4.8 ml of ethyl chloroformate was added dropwise. Themixture was stirred overnight at room temperature. The reaction mixturewas poured into about 300 ml of water, and extracted with diethyl ether.The ethereal layer was washed with water, dilute hydrochloric acid andwater in this order, dried and concentrated to give a yellow liquid.This liquid was chromatographed on a silica gel column usinghexane/ethyl acetate as an eluent to give 7.21 of a slightly yellowliquid. The NMR analysis of this liquid shoed that the signal (doublet,δ=4.08) assigned to --CH₂ OH of the starting polyprenol disappeared, anda signal (doublet, δ=4.45) assigned to --CH₂ O and signals (triplet,δ=1.20 and quartet, δ=4.05) assigned to ##STR57## newly appeared. TheFD-MASS analysis of this product gave m/e=1314. From these analyticaldata, the liquid was determined to be polyprenyl ethyl carbonate ofgeneral formula (II) in which n is 15 and A₂ is ##STR58## .

By a similar operation to that described hereinabove, a polyprenyl ethylcarbonate in which n is other than 15 and a polyprenyl ethyl carbonatemixture in which n distributes arbitrarily between 11 and 19 weresynthesized.

EXAMPLE 28

Synthesis of polyprenyl dimethyl carbamate:

2.48 g of polyprenol of general formula (III) in which n is 15 and X is--OH was dissolved in 10 ml of anydrous tetrahydrofuran. The solutionwas cooled to 0° C., and with stirring, 1.4 ml of a 1.6M hexane solutionof n-butyllithium was added. At the same temperature, 0.2 ml ofdimethylcarbamoyl chloride was added. The mixture was stirred at 0° C.for 30 minutes and then at room temperature for 2 hours. The reactionmixture was poured into about 20 ml of water, and extracted with diethylether. The extract was washed with water, dried and concentrated to givea yellow liquid. The liquid was chromatographed on a silica gel columnusing hexane/ethyl acetate as an eluent to give 2.16 g of a slightlyyellow liquid. The NMR analysis of the liquid showed that the signal(doublet, δ=4.08) assigned to --CH₂ OH of the starting polyprenoldisappeared, and a signal (doublet, δ=4.42) assigned to --CH₂ O and asignal (singlet, δ=2.80) assigned to ##STR59## newly appeared. TheFD-MASS analysis of this liquid gave m/e=1313. From these analyticaldata, this liquid was determined to be polyprenyl dimethyl carbamate ofgeneral formula (II) in which n is 15 and A₂ is ##STR60##

By a similar operation to that described above, a polyprenyl dimethylcarbamate in which n is other than 15 and a polyprenyl dimethylcarbamate mixture in which n distributes arbitrarily between 11 and 19were synthesized.

EXAMPLE 29

Synthesis of polyprenyl triethyl ammonium bromide:

2.6 g of polyprenyl bromide of general formula (II) in which n is 15 andA₂ is Br was added to 10 ml of anhydrous triethylamine, and the mixturewas left to stand overnight at room temperature. Consequently, a paleyellow waxy material precipitated. The precipitate was separated andwashed thoroughly with anhydrous diethyl ether. The solvent was removedunder reduced pressure to give 2.35 g of a pale yellow waxy product. TheNMR analysis (DMSO-d₆) of this product showed that the signal (doublet,δ=3.91) assigned to --CH₂ Br of the starting polyprenyl bromidedisappeared, and a signal (doublet, δ=3.77) assigned to --CH₂ N andsignals (triplet, δ=1.14, and quartet, δ=3.22) assigned to --N(C₂ H₅)₃newly appeared. Since this waxy product was very hygroscopic, itselemental and IR analyses were impossible. FD-MASS analysis was alsoimpossible because the product was an ammonium salt. NMR analysis,however, led to the determination that this waxy product was the desiredpolyprenyl triethyl ammonium bromide of general formula (II) in which nis 15 and A₂ is N⊕(C₂ H₅)₃ Br⊖.

By a similar operation to that described above, a polyprenyl triethylammonium bromide in which n is other than 15 and a polyprenyl triethylammonium bromide mixture in which n distributes arbitrarily between 11and 19 were synthesized.

EXAMPLE 30

Synthesis of polyprenyl dimethyl sulfonium bromide:

2.6 g of polyprenyl bromide of general formula (II) in which n is 15 andA₂ is Br was added to 10 ml of dimethyl sulfide and the mixture was leftto stand overnight at room temperature. Consequently, a yellow waxymaterial precipitated. The precipitate was separated and washedthoroughly with anhydrous diethyl ether, and then the solvent wasremoved under reduced pressure to give 1.27 g of a yellow waxy product.The NMR analysis of this product showed that the signal (doublet,δ=3.91) assigned to --CH₂ Br of the starting polyprenyl bromidedisappeared, and a signal (doublet, δ=4.15) assigned to ##STR61## and asignal (singlet, δ=2.88) assigned to ⊕S(CH₃)₂ newly appeared. Since thisproduct was highly hygroscopic, its elemental analysis was impossible.FD-MASS analysis was also impossible because the product was a sulfoniumsalt. The NMR analysis, however, led to the determination that theproduct was the desired polyprepyl dimethyl sulfonium bromide of generalformula (II) in which n is 15 and A₂ is ⊕--S(CH₃)₂ Br⊖.

By a similar operation to that described above, polyprenyl dimethylsulfonium bromide in which n is other than 15 and a polyprenyl dimethylsulfonium bromide mixture in which n distributes arbitrarily between 11and 19 were synthesized.

EXAMPLE 31

A three-necked flask purged with argon was charged with 0.316 g (13millimoles) of magnesium flakes, 0.5 ml of anhydrous tetrahydrofuran and0.08 ml of 1,2-dibromoethane, and they were heated by a dryer untilvigorous bubbling occurred. A solution of 2.51 g (10 millimoles) of2-[m4-bromo-3-methylbutoxy]-tetrahydro-2H-pyrane in 3.0 ml of anhydroustetrahydrofuran was added dropwise to the activated magnesium at such aspeed that the solvent was just boiled. Then, 60 ml of anhydroustetrahydrofuran was added to from a Grignard solution.

Another three-necked flask purged with argon was charged with a solutionof 6.42 g (5 millimoles) of the polyprenyl acetate of general formula(III) in which n is 15 and X is --COCH₃ produced in the same way as inExample 6 in 15 ml of anhydrous tetrahydrofuran, and 2.0 ml of a 0.1Manhydrous tetrahydrofuran solution of Li₂ CuCl₄. Then, the Grignardsolution prepared as above was added dropwise at 0° C. over 1 hour, andthen the mixture was stirred at 0° C. for 2 hours. Thereafter, asaturated aqueous solution of ammonium chloride was added to thereaction mixture to perform hydrolysis, and the product was extractedwith diethyl ether. The diethyl ether layer was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous magnesiumsulfate. The solvent was then removed by means of a rotary evaporator togive 7.95 g of a pale yellow liquid. By silica gel thin-layerchromatography (hexane/ethyl acetate=97/3 as a developing solvent), thisliquid was found to have a main spot at Rf=0.35. The FD-MASS analysis ofthe pale yellow liquid did not give m/e=1284 which showed the presenceof the starting polyprenyl acetate, but gave m/e=1396 as a main peakwhich showed the presence of the desired compound of general formula (V)in which Z is a tetrahydro-2H-pyranyloxymethyl group.

The pale yellow liquid was then dissolved in 40 ml of hexane, and 0.13 g(0.5 millimole) of pyridinium p-toluenesulfonate and 20 ml of ethanolwere added. The solution was heated at 55° C. for 3 hours with stirring.The reaction mixture was cooled, and then neutralized with 0.21 g ofsodium carbonate. The solvent was distilled off by a rotary evaporator.The resulting concentrate was dissolved in diethyl ether, washed with asaturated aqueous solution of sodium bicarbonate and then with asaturated aqueous solution of sodium chloride, and then dried overanhydrous magnesium sulfate. The solvent was removed by means of arotary evaporator. The remaining oily substance was heated at 150° C.and 0.5 torr for 30 minutes to remove low-boiling components. Theremaining oil was chromatographed on a silica gel column usinghexane/ethyl acetate (9/1) as an eluent to give 5.64 g of a colorlesstransparent liquid. By silica gel thin-layer chromatography(hexane/ethyl acetate=9/1 as a developing solvent), this liquid showed asingle spot at Rf=0.19. by the analytical data shown below, this liquidwas determined to be the desired compound of general formula (V) inwhich n is 15 and Z is --CH₂ OH.

FD-MASS: m/e=1312 (calculated 1312).

IR (cm⁻¹): 830, 1060, 1376, 1440, 2850, 2920, 3320.

¹³ C-NMR (ppm/intensity): 135.365/430, 135.229/3567, 135.005/349,134.937/290, 131.210/213, 125.071/5242, 124.993/499, 124.448/505,124.282/463, 124.214/445, 61.241/551, 40.029/541, 39.757/683,37.548/582, 32.245/5500, 32.021/456, 29.316/528, 26.825/492, 26.699/548,26.436/5166, 25.677/542, 25.308/567, 23.430/6330, 19.557/548,17.679/353, 16.006/640.

¹ H-NMR (ppm, signal form, proton ratio): 5.10 (b, 18H), 3.66 (m, 2H),2.03 (b, 70H), 1.68 (s, 48H), 1.60 (s, 9H), 1.80-1.10 (m, 5H), 0.91 (d,3H).

In the IR analysis an absorption at 907 cm⁻¹ was not detected, and in ¹H-NMR analysis, a signal at δ=5.78 ppm (double doublet) was not detectedat all. These absorptions show the formation of the isomerizationproduct described hereinabove.

The 2-[4-bromo-3-methylbutoxy]tetrahydro-2H-pyran used in the aboveprocedure was synthesized by the following method.

16.7 g of 4-bromo-3-methylbutanol was dissolved in 200 ml of anhydrousmethylene chloride, and with ice cooling, 10.0 g of dihydropyran wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 2 hours, and then the solvent was distilled off. Theresidue was purified by silica gel column chromatography usinghexane/ethyl acetate as an eluent to give 16.2 g of2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran. The NMR spectrum of thisproduct was as follows:

δ ppm: 1.00 (doublet, 3H), 1.20-2.20 (multiplet, 9H), 3.20-3.90(multiplet, 6H), 4.53 (broad, 1H).

EXAMPLES 32 to 34

Example 31 was repeated except that each of the polyprenyl compounds(n=15) shown in Table 6 was used instead of the polyprenyl acetate usedin Example 31. The results are shown in Table 6.

EXAMPLE 35

The procedure of Example 31 before the reaction with pyridiniump-toluenesulfonate was repeated except that 4-bromo-3-methylbutyl benzylether was used instead of the2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran and CuBr was used insteadof Li₂ CuCl₄. The resulting liquid product was heated at 130° C. and 0.5torr for 30 minutes to remove low-boiling components. Thus, 6.75 g of apale yellow liquid was obtained. This liquid was then purified by silicagel column chromatography using hexane/isopropyl ether (97/3 by volume)as an eluent to give 5.33 g of a slightly yellow liquid. In silica gelthin-layer chromatography (hexane/diisopropyl ether=95/5 by volume as adeveloping solvent), this liquid gave a single spot at Rf=0.59. From thefollowing analytical data, this liquid product was determined to be acompound of general formula (V) in which n is 15 and Z is --CH₂ OCH₂ C₆H₅.

FD-MASS: m/e=1402.

IR (cm⁻¹): 698, 735, 840, 1100, 1378, 1450, 1662, 2840, 2930, 2970.

¹ H-NMR (δ ppm, signal form, proton number ratio): 7.28 (s, 5H), 5.07(b, 18H), 4.42 (s, 2H), 3.45 (t, 2H), 2.04 and 2.00 (s, 70H), 1.62 (s,48H), 1.50 (s, 9H), 1.22 (b, 5H), 0.80 (b, 3H).

A three-necked flask purged with argon was cooled with ice-water, and 10ml of anhydrous ethylamine was introduced into the flask. Then, 0.10 g(15 mg-atom) of lithium was added, and the contents of the flask werestirred at 0° C. for 10 minutes to give a blue solution. A solution ofthe pale yellow liquid obtained as above in anhydrous tetrahydrofuranwas added dropwise over 10 minutes to the resulting blue solution. Themixture was stirred at 0° C. for 30 minutes, and diethyl ether and anaqueous saturated solution of ammonium chloride were added to performhydrolysis. The ethereal layer was washed with 1N hydrochloric acid, asaturated aqueous solution of sodium bicarbonate and a saturated aqueoussolution of sodium chloride, and dried over anhydrous magnesium sulfate.The solvent was distilled off. The remaining liquid product was purifiedby silica gel column chromatography using hexane/ethyl acetate (9/1 byvolume) as an eluent to give 4.80 g of a colorless transparent liquid.The Rf value in silica gel thin-layer chromatography, FD-MASS, IR, ¹³C-NMR and ¹ H-NMR data of this product were identical with those of theliquid product obtained in Example 31. In the IR analysis, an absorptionat 907 cm⁻¹ was not detected at all, and in the ¹ H-NMR analysis, asignal at δ=5.78 was not detected at all.

EXAMPLES 36 to 44

Example 35 was repeated except that each of the polyprenyl compounds(n=15) indicated in Table 6 was used instead of the polyprenyl acetateused in Example 35. The results are shown in Table 6. In Examples 42 and43, a weak absorption at 907 cm⁻¹ in the IR spectrum, and a weak signalat δ=5.78 ppm in the ¹ H-NMR were detected. This led to thedetermination that a small amount of the undesired isomer existed.

EXAMPLES 45 to 48

Example 35 was repeated except that each of the metal compoundsindicated in Table 6 was used instead of cuprous bromide. The resultsare shown in Table 6.

EXAMPLE 49

A three-necked flask purged with argon was charged with 0.474 g (19.5millimoles) of magnesium flakes, 0.5 ml of anhydrous tetrahydrofuran and0.08 ml of 1,2-dibromoethane. They were heated by a dryer until vigorousbubbling occurred. A solution of 3.86 g (15 millimoles) of4-bromo-3-methylbutyl benzyl ether in 4.5 ml of anhydroustetrahydrofuran was added dropwise to the activated magnesium at such aspeed that the solvent was just boiling. After the addition, the mixturewas stirred at 70° C. for 30 minutes, and 25 ml of anhydroustetrahydrofuran was added to form a Grignard solution.

Another three-necked flask purged with argon was charged with 1.43 g(7.5 millimoles) of anhydrous cuprous iodide and 40 ml of anhydroustetrahydrofuran. The flask was then cooled to -30° C. in a dryice-acetone bath. The Grignard solution prepared as above was addeddropwise to the resulting suspension at -30° C., and after the addition,the mixture was stirred at -30° C. for 20 minutes.

A solution of 6.42 g (5 millimoles) of the polyprenyl acetate of generalformula (III) in which n is 15 and X is --OCOCH₃ produced in the sameway as in Example 6 in 10 ml of anhydrous tetrahydrofuran was addeddropwise at -30° C. to the resulting white suspension. The reactionmixture was gradually brought to room temperature, and stirred at roomtemperature for 10 hours.

Then, a saturated aqueous solution of ammonium chloride was added to thereaction mixture to perform hydrolysis. It was then extracted withdiethyl ether. The ethereal layer was washed with a saturated solutionof ammonium chloride and dried over anhydrous magnesium sulfate. Thesolvent was distilled off. The resulting pale yellow liquid was heatedat 130° C. and 0.5 torr for 30 minutes to remove low-boiling components.The residue was purified by silica gel column chromatography usinghexane/diisopropyl ether (97/3) as an eluent to give 4.63 g of aslightly yellow liquid. This yellow liquid gave a single spot at Rf=0.59in silica gel thin-layer chromatography (using hexane/diisopropylether=95/5 as a developing agent). The FD-MASS analysis of the productgave m/e=1402. These analytical data were identical with those of thecompound of general formula (V) in which n is 15 and Z is CH₂ OCH₂ C₆ H₅obtained in Example 35.

The resulting liquid was subjected to a reaction of removing the benzylgroup by the same operation as in Example 35. The product was purifiedby silica gel column chromatography using hexane/ethyl acetate (9/1) asan eluent to give 4.15 g of a colorless clear liquid. The Rf value insilica gel thin-layer chromatography (hexane/ethyl acetate=9/1 as adeveloping solvent) and the m/e value in FD-MASS of this liquid wereidentical with those of the compound of general formula (V) in which nis 15 and Z is CH₂ OH obtained in Example 31. But a weak absorption wasnoted at 907 cm⁻¹ in IR analysis and δ=5.78 ppm in ¹ H-NMR.

EXAMPLES 50 and 51

Example 49 was repeated except that each of the polyprenyl compounds(n=15) shown in Table 6 was used instead of the polyprenyl acetate usedin Example 49. In both of Examples 50 and 51, the IR analysis and theNMR analysis showed the presence of a small amount of the undesiredisomer.

EXAMPLE 52

Example 35 was repeated except that polyprenyl bromide (n=15) was usedinstead of the polyprenyl acetate, cuprous bromide was not used, andafter the addition of the Grignard solution, the reaction was carriedout at the refluxing temperature of tetrahydrofuran for 9 hours insteadof carrying it out at 0° C. for 2 hours. The results are shown in Table6.

EXAMPLES 53 to 55

Example 52 was repeated except that the other polyprenyl compounds(n=15) indicated in Table 6 were used instead of the polyprenyl bromide.The results are shown in Table 6.

    TABLE 6          Amount     Reaction of the Formation of Compound (III) Compound     (IV) Metal catalyst temp. reaction undesired Example X Amount (g) Y Z     Amount (g) Type Amount and time product (g) isomer (*)                  31 OAc 6.42 MgBr      ##STR62##      2.51 Li.sub.2 CuCl.sub.4 0.1 Msolution2.0 ml 0° C. 2 hr 5.64 O     32 OCOC.sub.2 H.sub.5 6.49 " " " " " " 5.35 O 33 OCOC.sub.17 H.sub.23     7.53 " " " " " " 3.94 O 34 OCOC.sub.6 H.sub.5 6.73 " " " " " " 5.23 O 35     OAc 6.42 " CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5 2.57 CuBr 0.029 g "  4.80     O 36 OCO.sub.2 C.sub.2      H.sub.5 6.36 " " " " " " 4.26 O 37 OCON(CH.sub.3).sub.2 6.56 " " " " "     " 4.10 O 38 OCOCH.sub.2 Cl 6.59 " " " " " " 3.93 O 39 OCOCF.sub.3 6.69     MgBr CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5 2.57 CuBr 0.029 g 0° C. 2     hr 3.80 O 40 OCOH 6.35 " " " " " " 0.52 O 41 N.sup.⊕ (C.sub.2     H.sub.5).sub.3 Br.sup.⊖ 7.03 " " " " " " 2.76 O 42 S.sup.⊕     (CH.sub.3).sub.2 Br.sup.⊖ 6.83 " " " " " " 4.23 Δ 43 Br     7.61 " " " " " " 4.41 Δ 44 SO.sub.2 C.sub.6 H.sub.5 6.83 " " " " "     " 1.31 O 45 OAc 6.42 " " " CuI 0.038 " 4.75 O 46 OAc 6.42 " " " Cu(AcAc).     sub.2.sup.(**) 0.052 " 4.62 O 47 OAc 6.42 " " " NiCl.sub.2.sup.(***)     0.136 " 0.79 O       (dppf) 48 OAc 6.42 " " " PdCl.sub.2 0.146 " 0.27 O          (dppf) 49 OAc 6.42 " " " CuI 1.43 room temp. 4.15 Δ     10 hr.      50     ##STR63##      6.67 MgBr CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5 2.57 CuI 1.43 room temp.10     hr. 2.96 Δ      51     ##STR64##      6.71 " " " " " " 4.23 Δ  52 Br 7.61 " " " None None Refluxing     0.72 O         of THF         9 hrs.      53     ##STR65##      6.87 " " " " " " 3.35 O      54     ##STR66##      6.59 " " " " " " 3.18(****) O  55 OPO(OC.sub.2 H.sub.5).sub.2 6.89 " "     " " " " 3.01 Δ     (*) O: The absence of the isomer was ascertained by IR and .sup.1 HNMR     analyses;     Δ: The presence of a small amount of the isomer was ascertained by     the same analyses.     (**): AcAc = acetylacetonato group.     (***): dppf = 1,1'-diphenylphosphinoferrocene.     (****): The reaction was carried out using MgBr.sub.2 (1.84 g).

EXAMPLE 56

A three-necked flask purged with argon was charged with 1.7 g (0.25gram-atom) of lithium and 40 ml of anhydrous ether, and a solution of25.1 g (100 millimoles) of2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 20 ml of anhydrousdiethyl ether was first added in a small amount. After ascertaining thatheat was generated, the mixture was cooled to 0° C. and the remainder ofthe solution was added dropwise. After the addition, the mixture wasstirred at 10° C. for 2 hours.

Separately, 990.6 mg (5.2 millimoles) of anhydrous cuprous iodide and 20ml of anhydrous diethyl ether were put in another three-necked flaskpurged with argon, and the lithium reagent solution (corresponding to 10millimoles) prepared as above was added dropwise at -10° C. over 10minutes. The mixture was stirred further for 15 minutes at thistemperature. A solution of 3.21 g (2.5 millimoles) of polyprenyl acetateof general formula (III) in which n is 15 and X is --OCOCH₃ in 15 ml ofanhydrous diethyl ether was added dropwise at -10° C. over 20 minutes.Furthermore, at this temperature, the mixture was stirred for 1 hour.The reaction mixture was hydrolyzed by adding a saturated aqueoussolution of ammonium chloride, and extracted with diethyl ether. Theethereal layer was washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent wasremoved by means of a rotary evaporator to give 5.09 g of a pale yellowliquid. This product had a main spot at Rf=0.36 in silica gel thin-layerchromatography (hexane/ethyl acetate=97/3 as a developing solvent.) TheFD-MASS analysis of this product gave m/e=1396.

The liquid product was reacted with pyridinium p-toluenesulfonate andthen worked up in the same way as in Example 31 to give 2.12 g of acolorless clear liquid. The results of its silica gel thin-layerchromatography, FD-MASS, IR and ¹ H-NMR analyses were the same as thoseobtained in Example 31.

EXAMPLE 57

Example 56 was repeated except that polyprenyl phenylsulfoxide in whichn is 15 and X is S(O)C₆ H₅ was used instead of the polyprenyl acetate.Thus, 1.15 g of a colorless clear liquid was obtained. The results ofits silica gel thin-layer chromatography and FD-MASS analysis were thesame as those obtained in Example 56.

EXAMPLE 58

Example 56 was repeated except that polyprenyl phenyl sulfone in which nis 15 and X is S(O)₂ C₆ H₅ was used instead of the polyprenyl acetate.Thus, 1.38 g of a colorless clear liquid was obtained. The results ofits silica gel thin-layer chromatography and FD-MASS analysis were thesame as those obtained in Example 56.

EXAMPLE 59

A three-necked flask purged with argon was charged with 1.7 g (0.25gram-atom) of lithium and 40 ml of anhydrous diethyl ether, and asolution of 25.1 g (100 millimoles of2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 20 ml of anhydrousdiethyl ether was added in a small amount. After ascertaining that heatwas generated, the mixture was cooled to 0° C., and the remainder of thesolution was added dropwise. After the addition, the mixture was stirredat 10° C. for 2 hours.

Another three-necked flask purged with argon was charged with 3.80 g(2.5 millimoles) of polyprenyl bromide of general formula (III) in whichn is 15 and X is Br and 10 ml of anhydrous diethyl ether, and thelithium reagent solution (corresponding to 10 millimoles) prepared asabove was added dropwise at 0° C. over 10 minutes, and then the mixturewas stirred for 10 hours at room temperature.

The reaction mixture was then hydrolyzed by adding a saturated aqueoussolution of ammonium chloride, and extracted with diethyl ether. Theethereal layer was washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent wasremoved by means of a rotary evaporator to give 5.46 g of a pale yellowliquid.

The liquid was reacted with pyridinium p-toluenesulfonate and worked upin the same way as in Example 31 to give 0.44 g of a colorless clearliquid. The results of its silica gel thin-layer chromatography andFD-MASS analysis were the same as those obtained in Example 31.

EXAMPLE 60

(A) A three-necked flask purged with argon was charged with 1.7 g (0.25gram-atom) of lithium and 40 ml of anhydrous diethyl ether and asolution of 25.1 g (100 millimoles) of2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 20 ml of anhydrousdiethyl ether was added in a small amount. After ascertaining that heatwas generated, the mixture was cooled to 0° C., and the remainder of thesolution was added dropwise. After the addition, the mixture was stirredat 10° C. for 2 hours.

(B) A solution of 3.11 g (2.5 millimoles) of polyprenol of generalformula (III) in which n is 15 and X is --OH in 5 ml of anhydrousdiethyl ether was put in another three-necked flask purged with argon,and at 0° C. a diethyl ether solution of methyl lithium (1.3moles/liter, 1.9 ml, 2.5 millimoles) was added dropwise. After theaddition, the mixture was stirred at 0° C. for 20 minutes.

Then, the other three-necked flask purged with argon was charged with0.48 g (2.5 millimoles) of anhydrous cuprous iodide and 6 ml ofanhydrous tetrahydrofuran, and the diethyl ether solution prepared in(B) was added dropwise at room temperature. After the solution, themixture was stirred at room temperature for 30 minutes, and then cooledto -65° C. in a dry ice-acetone bath.

Then, the lithium reagent solution (corresponding to 10 millimoles)prepared in (A) above was added dropwise at this temperature, andsubsequently, a solution of 1.24 (2.5 millimoles) ofN,N-methylphenylaminotriphenyl phosphonium iodide in 13 ml of anhydrousN,N-dimethylformamide was added dropwise. After the addition, themixture was stirred at -65° C. for 1 hour, and gradually brought to roomtemperature. It was then stirred at room temperature for 2 hours.

The reaction mixture was hydrolyzed by adding a saturated aqueoussolution of ammonium chloride, and extracted with diethyl ether. Theethereal layer was washed with 0.2N hydrochloric acid and dried overanhydrous magnesium sulfate. The solvent was removed by means of arotary evaporator and the residue was mixed with 50 ml of hexane. Then,the precipitated triphenyl phosphine oxide was filtered off and thefiltrate was concentrated to give 3.49 g of a pale yellow liquid.

The liquid was reacted with pyridinium p-toluenesulfonate and worked upin the same way as in Example 31 to give 2.10 g of a colorless clearliquid. The results of silica gel thin-layer chromatography, FD-MASS,IR, ¹ H-NMR and ¹³ C-NMR analyses were the same as those obtained inExample 31.

EXAMPLE 61

A three-necked flask purged with argon was charged with 0.316 g (13millimoles) of magnesium flakes, 0.5 ml of anhydrous tetrahydrofuran and0.08 ml of 1,2-dibromoethane and they were heated by a dryer untilvigorous bubbling occurred. Then, a solution of 4.05 g (10 millimoles)of 4-(t-butyl diphenyl silyloxy)-2-methylbutyl bromide in 5.0 ml ofanhydrous tetrahydrofuran was added dropwise to the activated magnesiumat such a speed that the solvent was just boiling. After the addition,the mixture was stirred at 70° C. for 30 minutes. Then, 60 ml ofanhydrous tetrahydrofuran was added to form a Grignard solution.

Another three-necked flask purged with argon was charged with a solutionof 6.42 g (5 millimoles) of polyprenyl acetate of general formula (III)in which n is 15 and X is --OCOCH₃ in 15 ml of anhydrous tetrahydrofuranand an anhydrous tetrahydrofuran solution of Li₂ CuCl₄ (0.1M solution,2.0 ml). The Grignard solution prepared as above was added dropwise at0° C. for 1 hour, and the mixture was stirred at 0° C. for 2 hours.Then, the reaction mixture was hydrolyzed by adding a saturated aqueoussolution of ammonium chloride, and extracted with diethyl ether. Theethereal layer was washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent wasremoved by means of a rotary evaporator to give an oily product. Theoily product was heated at 130° C. and 0.5 torr for 30 minutes to removelow-boiling components. The residue was then purified by silica gelcolumn chromatography using hexane/ethyl acetate as an eluent to give4.27 g of a colorless clear liquid. The FD-MASS analysis of this liquidwas m/e=1550. This liquid was then dissolved in 30 ml oftetrahydrofuran, and with stirring at room temperature, 5 g oftetra-n-butyl ammonium fluoride was added in small portions. The mixturewas then stirred at room temperature for 2 hours. The tetrahydrofuranwas distilled off, and about 50 ml of diethyl ether was added. Theethereal layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The diethyl etherwas distilled off to give a liquid. The liquid was purified by silicagel column chromatography using hexane/ethyl acetate (9/1) as an eluentto give 3.82 g of a colorless clear liquid. In silica gel thin-layerchromatography (hexane/ethyl acetate=9/1 as a developing solvent), thisliquid gave the same Rf value as the compound obtained in Example 31.The results of its FD-MASS, IR, ¹ H-NMR and ¹³ C-NMR analyses were thesame as those obtained in Example 31. Accordingly, this liquid wasdetermined to be a compound of general formula (V) in which n is 15 andZ is --CH₂ OH.

The 4-(t-butyl-diphenyl-silyloxy)-2-methylbutyl bromide used above wassynthesized by the following procedure.

16.7 g of 4-bromo-3-methylbutanol was dissolved in 500 ml of anhydrousmethylene chloride, and 13.2 g of triethylamine and 500 mg of4-dimethylaminopyridine were added. At room temperature, 33.0 g oft-butyldiphenylsilyl chloride was added dropwise. After the addition,the mixture was stirred overnight at room temperature, poured intowater, and extracted with diethyl ether. The ethereal layer wasthoroughly washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The diethyl ether wasdistilled off to give an oily product. The oily product was purified bychromatography using a column of silica gel CC-7 (a product ofMallinckrodt) and hexane/diethyl ether as an eluent to give 38.1 g of acolorless clear liquid. The IR analysis of this liquid showed that theabsorption at about 3300 cm⁻¹ attributed to the OH group of the startingmaterial disappeared. In its NMR analysis, signals were observed atδ0.90 (3H, doublet), 1.02 (9H, singlet), 1.1-1.7 (2H, multiplet),1.7-2.2 (1H, multiplet), 3.22 (doublet, 2H), 3.63 (2H, triplet), 7.1-7.4(5H, multiplet) and 7.4-7.8 (5H, multiplet). Accordingly, this liquidproduct was determined to be the desired4-(t-butyldiphenylsilyloxy)-2-methylbutyl bromide.

EXAMPLE 62

A three-necked flask purged with argon was charged with 0.316 g (13millimoles) of magnesium flakes, 0.5 ml of anhydrous tetrahydrofuran and0.08 ml of 1,2-dibromoethane, and they were heated by a dryer untilvigorous bubbling occurred. Then, a solution of 1.81 g (10 millimoles)of 4-methoxy-2-methylbutyl bromide in 3.0 ml of anhydroustetrahydrofuran was added dropwise to the activated magnesium at such aspeed that the solvent was just boiled. After the addition, the mixturewas stirred at 70° C. for 15 minutes. Then, 60 ml of anhydroustetrahydrofuran was added to form a Grignard solution.

Another three-necked flask purged with argon was charged with a solutionof 6.42 g (5 millimoles) of polyprenyl acetate of general formula (III)in which n is 15 and X is --OCOCH₃ in 15 ml of anhydrous tetrahydrofuranand an anhydrous tetrahydrofuran solution of Li₂ CuCl₄ (0.1M solution,2.0 ml), and the Grignard solution prepared as above was added dropwiseat 0° C. for 1 hour. The mixture was stirred at 0° C. for 2 hours. Then,the reaction mixture was hydrolyzed by adding a saturated aqueoussolution of ammonium chloride, and extracted with diethyl ether. Theethereal layer was washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off by means of a rotary evaporator. The resulting oilyproduct was heated at 130° C. and 0.5 torr for 30 minutes to removelow-boiling components, and then purified by silica gel columnchromatography using hexane/ethyl acetate as an eluent to give 4.72 g ofa colorless clear liquid. The FD-MASS analysis of this product showed apeak at m/e=1326. Hence, this liquid was determined to be the desiredcompound of general formula (V) in which n is 15 and Z is --CH₂ OCH₃.

Then, this liquid was dissolved in 10 ml of anhydrous methylene chlorideand in an atmosphere of argon, 1.30 g (6.5 millimoles) ofiodotrimethylsilane was added at room temperature. The mixture wasstirred at room temperature for 10 hours. Then, 1 ml of methanol wasadded, and the mixture was stirred for 20 minutes. The solvent wasremoved by means of a rotary evaporator, and the remaining liquid wasdissolved in diethyl ether. The ethereal layer was washed with anaqueous solution of sodium bisulfite, an aqueous solution of sodiumbicarbonate and an aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresulting liquid product was purified by silica gel columnchromatography using hexane/ethyl acetate=9/1 as an eluent to give 3.28g of a colorless clear liquid. The Rf value in silica gel thin-layerchromatography (hexane/ethyl acetate=9/1 as a developing solvent), them/e value in FD-MASS and the IR, ¹ H-NMR and ¹³ C-NMR data of thisliquid were identical with those of the compound of general formula (V)in which n is 15 and Z is --CH₂ OH obtained in Example 31.

The 4-methoxy-2-methylbutyl bromide was synthesized in the followingmanner.

30.7 g of 50% sodium hydride was suspended in 400 ml of tetrahydrofuran,and a solution of 50.0 g of 3-methyl-3-buten-1-ol in 50 ml oftetrahydrofuran was added. The mixture was heated under reflux for 2hours, and under ice cooling, a solution of 90.8 g of methyl iodide in50 ml of tetrahydrofuran was added dropwise. The mixture was stirredovernight at room temperature. The reaction mixture was poured intowater and extracted with diethyl ether. The ethereal layer was washedwith water and a saturated aqueous solution of sodium chloride, anddried over anhydrous magnesium sulfate. The solvent was carefullydistilled off, and the residue was fractionally distilled underatmospheric pressure to give 66.5 g of a liquid as a fraction boiling at99° to 102° C. The IR analysis of this liquid showed that the absorptionat about 3300 cm⁻¹ attributed to the OH group of the starting alcoholdisappeared. In its NMR analysis, signals were observed at δ1.69(singlet, 3H), 2.3 (triplet, 2H), 3.26 (singlet, 3H) 3.57 (triplet, 2H)and 4.71 (broad singlet, 2H). The GC-MASS analysis gave m/e=100. Fromthe above analytical data, this liquid was determined to be3-methyl-3-butenyl methyl ether.

2.5 g of sodium borohydride was suspended in 320 ml of tetrahydrofuran,and 20.0 g of 3-methyl-3-butenyl methyl ether was added dropwise. Then,10.1 ml of boron trifluoride-diethyl ether complex was added dropwise at25° C. The mixture was stirred for 1 hour, and then cooled to 0° C.42.56 g of bromine and 64.0 g of a 28 wt. % methanol solution of sodiummethoxide were added dropwise below 5° C. through two different droppingfunnels. The reaction mixture was stirred further at room temperaturefor 20 minutes, and then 100 ml of a saturated aqueous solution ofsodium bicarbonate was added. Water was further added until the whiteprecipitate disappeared. The organic layer was separated. The waterlayer was extracted with diethyl ether. The organic layers werecombined, and washed with a saturated aqueous solution of sodiumthiosulfate, a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride in this order, and thendried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was distilled under reduced pressure to give 22.5 g of acolorless clear liquid as a fraction boiling at 60° C./5 mmHg. In theNMR analysis of this liquid, signals were observed at δ0.96 (doublet,3H), 1.38-2.10 (multiplet, 3H), 3.31 (singlet, 3H), and 3.35-3.60(multiplet, 4H). From these data, this liquid was determined to be thedesired 4-methoxy-2-methylbutyl bromide.

EXAMPLE 63

A three-necked flask purged with argon was charged with 0.316 g (13millimoles) of magnesium flakes, 0.5 ml of anhydrous tetrahydrofuran and0.08 ml of 1,2-dibromoethane, and they were heated by a dryer untilvigorous bubbling occurred. Then, a solution of 2.11 g (10 millimoles)of 4,4-dimethoxy-2-methylbutyl bromide in 3.0 ml of anhydroustetrahydrofuran was added dropwise to the activated magnesium at such aspeed that the solvent was just boiling. The mixture was then stirred at70° C. for 30 minutes. Then, 60 ml of anhydrous tetrahydrofuran wasadded to form a Grignard solution.

Another three-necked flask purged with argon was charged with 6.42 g (5millimoles) of polyprenyl acetate of general formula (III) in which n is15 of X is --OCOCH₃ and an anhydrous tetrahydrofuran solution of Li₂CuCl₄ (0.1M solution, 2.0 ml). The Grignard solution prepared as abovewas added dropwise at 0° C. over 1 hour. The mixture was then stirred at0° C. for 2 hours. The reaction mixture was hydrolyzed by adding asaturated aqueous solution of ammonium chloride and extracted withdiethyl ether. The ethereal layer was washed with a saturated aqueoussolution of sodium chloride, and dried over anhydrous magnesium sulfate.The solvent was distilled off by means of a rotary evaporator to give7.67 g of a pale yellow liquid. When this liquid was subjected toFD-MASS analysis, the peak at m/e=1284 showing the presence of thestarting polyprenyl acetate was very weak, and m/e=1356 showing thedesired compound of formula (V) in which n is 15 and Z is --CH(OCH₃)₂was detected as a main peak.

The pale yellow liquid was then put in a mixture of 30 ml oftetrahydrofuran and 10 ml of 10% hydrochloric acid, and the mixture wasstirred at room temperature for 5 hours. The reaction mixture wassubjected to a rotary evaporator to remove tetrahydrofuran, and theresidue was extracted with diethyl ether. The ethereal layer was washedwith a saturated aqueous solution of sodium chloride, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride in this order, and dried over anhydrous magnesiumsulfate. The diethyl ether was distilled off by means of a rotaryevaporator to give 7.29 g of a pale yellow liquid. In the FD-MASSanalysis of this liquid, m/e=1310 was detected as a main peak. This ledto the determination that this liquid was a compound of formula (V) inwhich n is 15 and Z is --CHO.

This liquid was then dissolved in a mixture of 20 ml of hexane and 10 mlof ethanol, and 1.0 g of sodium borohydride was added at roomtemperature. The mixture was stirred for 1 hour. The solvent was thenremoved by means of a rotary evaporator, and about 50 ml of diethylether was added to the residue. The ethereal layer was washed with asaturated aqueous solution of sodium chloride, and dried over anhydrousmagnesium sulfate. The solvent was removed by means of a rotaryevaporator. The remaining oily substance was heated at 150° C. and 0.5torr for 30 minutes to remove low-boiling components. The remaining oilysubstance was purified by silica gel column chromatography usinghexane/ethyl acetate (9/1) as an eluent to give 4.25 g of a colorlessclear liquid. The results of its IR, ¹ H-NMR, ¹³ C-NMR and FD-MASS wereidentical with those of the compound of general formula (V) in which nis 15 and Z is --CH₂ OH obtained in Example 31.

The 4,4-dimethoxy-2-methylbutyl bromide used above was synthesized bythe following procedure.

20.9 g of ethyl 4-bromo-3-methyl butyrate was dissolved in 400 ml ofanhydrous toluene, and the solution was stirred at -78° C. In anatmosphere of nitrogen, diisobutyl aluminum hydride 1M solution, 120 ml)was added dropwise, and the mixture was stirred at -78° C. for 30minutes. Methanol was then added carefully to decompose the excess ofthe reducing reagent. The product was diluted with 400 ml of diethylether, and 100 ml of water was added. The mixture was stirred at roomtemperature for 2 hours. The solution was filtered through Celite, andthe aqueous layer was extracted with diethyl ether. The organic layerswere combined, washed with an aqueous solution of sodium chloride, anddried over anhydrous magnesium sulfate. The solvent was distilled off togive 14.8 g of a crude oily product. The IR analysis of this oilyproduct showed that weak absorptions at 2820 and 2720 cm⁻¹ and a strongabsorption at 1720 cm⁻ 1, characteristic of the --CHO group, wereobserved. In the NMR analysis, a signal assigned to --CHO was observedat δ=9.60.

The crude oily product was dissolved in 300 ml of methanol, and 500 mgof p-toluenesulfonic acid was added. The mixture was stirred at roomtemperature for 2 hours. The reaction mixture was neutralized by addingsodium bicarbonate, and concentrated under reduced pressure. The residuewas poured into water, and extracted with diethyl ether. The ethereallayer was washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The diethyl ether wasdistilled off to give 18 g of a crude oily product. The oily product waspurified by silica gel column chromatography using hexane/diethyl etheras an eluent to give 17.2 g of a colorless clear liquid. The IR analysisof this liquid showed that the characteristic absorptions at 2820, 2720and 1720 cm⁻¹ attributed to --CHO disappeared, and several absorptionsattributed to the acetal appeared at 1200 to 1000 cm⁻¹. In the NMRanalysis, signals were observed at δ1.00 (3H, doublet), 1.1-1.7 (2H,multiplet), 1.7-2.0 (1H, multiplet), 3.22 (6H, singlet), 3.31 (2H,multiplet), and 4.32 (1H, triplet). The GC-MASS analysis gave m/e=210.From these analytical data, this liquid was determined to be4,4-dimethoxy-2-methylbutyl bromide.

EXAMPLE 64

A three-necked flask purged with argon was charged with 0.316 g (13millimoles) of magnesium flakes, 0.5 ml of anhydrous tetrahydrofuran and0.08 ml of 1,2-dibromoethane, and they were heated by a dryer untilvigorous bubbling occurred. Then, a solution of 2.43 g (10 millimoles)of 4,4-dimethylthio-2-methylbutyl bromide in 3.0 ml of anhydroustetrahydrofuran was added dropwise to the activated magnesium at such aspeed that the solvent was just boiled. After the addition, the mixturewas stirred at 70° C. for 15 minutes. Then, 60 ml of anhydroustetrahydrofuran was added to form a Grignard solution.

A three-necked flask purged with argon was charged with a solution of6.42 g (5 millimoles) of polyprenyl acetate of general formula (III) inwhich n is 15 and X is --OCOCH₃ in 15 ml of anhydrous tetrahydrofuranand an anhydrous tetrahydrofuran solution of Li₂ CuCl₄ (0.1M solution,2.0 ml). The Grignard solution prepared as above was added dropwise at0° C. over 1 hour, and the mixture was then stirred at 0° C. for 2hours. The reaction mixture was hydrolyzed by adding a saturated aqueoussolution of ammonium chloride, and extracted with diethyl ether. Theethereal layer was washed with an aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The solvent was distilledoff by means of a rotary evaporator. The resulting oily product washeated at 150° C. and 0.3 torr for 30 minutes to remove low-boilingcomponents. The FD-MASS analysis of the remaining yellow liquid showedthat a peak was detected at m/e=1388 which showed the presence of thecompound of formula (V) in which n is 15 and Z is CH(SCH₃)₂.

The oily product was dissolved in 20 ml of acetone, and 1 ml of water,0.25 g of mercuric chloride and 0.25 g of cadmium carbonate were added.The mixture was stirred at room temperature for 25 hours, and further0.10 g of mercuric chloride and 0.10 g of cadmium carbonate were added,the mixture was stirred for 20 hours further. The precipitate wasremoved by filtration, and acetone was distilled off. The remainingliquid was dissolved in diethyl ether. The ethereal layer was washedwith water, a 10% aqueous solution of potassium iodide, water, and asaturated aqueous solution of sodium chloride in this order, and driedover anhydrous magnesium sulfate. The solvent was distilled off, and theresidue was dissolved in 20 ml of hexane and 10 ml of ethanol. To thesolution was added 1.0 g of sodium borohydride at room temperature andthe mixture was stirred for 1 hour. The solvent was distilled off, anddiethyl ether and a saturated aqueous solution of ammonium chloride wereadded to the residue. The aqueous layer was extracted with diethylether. The ethereal layer was washed with a saturated aqueous solutionof sodium chloride, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the remaining oily product was heated at130° C. and 0.5 torr for 30 minutes to remove low-boiling components.The residue was purified by silica gel chromatography using hexane/ethylacetate (9/1) as an eluent to give 3.07 g of a colorless clear liquid.The Rf value in silica gel thin-layer chromatography (hexane/ethylacetate=9/1 as a developing solvent), the m/e value of FD-MASS, and theIR, ¹ H-NMR and ¹³ C-NMR of this liquid were identical with those of thecompound of general formula (V) in which n is 15 and Z is --CH₂ OHobtained in Example 31.

The 4,4-dimethylthio-2-methylbutyl bromide used above was synthesized bythe following procedure.

14.8 g of crude aldehyde obtained by reducing ethyl4-bromo-3-methylbutyrate with diisobutyl aluminum hydride at -78° C. inanhydrous toluene was dissolved in 200 ml of anhydrous diethyl ether. At0° C., 21.6 g of methylthiotrimethylsilane was added dropwise, and themixture was stirred at room temperature for 2 hours. Water was added,and the mixture was extracted with diethyl ether. The ethereal layer waswashed with a saturated aqueous solution of sodium chloride, and driedover anhydrous magnesium sulfate. The diethyl ether was distilled offand the resulting liquid was purified by silica gel columnchromatography using hexane/diethyl ether as an eluent to give 17.4 g ofa colorless clear liquid.

The IR analysis of this liquid showed that absorptions attributed to thestarting aldehyde were not observed at 2820, 2720, and 1720 cm⁻¹. In theNMR analysis, a signal (triplet, δ=3.83) assigned to ##STR67## and asignal (singlet, δ=2.08) assigned to ##STR68## were observed. TheGC-MASS analysis gave m/e=242.

From these analytical data, the liquid was determined to be the desired4,4-dimethylthio-2-methylbutyl bromide.

EXAMPLE 65

Example 35 was repeated except that anhydrous diethyl ether was usedinstead of the anhydrous tetrahydrofuran. Thus, 4.52 g of a colorlessclear liquid was obtained. The Rf value in silica gel thin-layerchromatography (hexane/ethyl acetate=9/1 as an eluent) and the m/e valuein FD-MASS of this liquid were identical with those of the compound ofgeneral formula (V) in which n is 15 and Z is --CH₂ OH obtained inExample 35. In the IR analysis, a weak absorption was observed at 907cm⁻¹.

EXAMPLE 66

Example 35 was repeated except that (S)-4-bromo-3-methylbutyl benzylether ([α]_(D) ²⁰ =+6.05°, c=1.10, ethanol) was used instead of the4-bromo-3-methylbutyl benzyl ether, and the polyprenyl acetate mixture,prepared by the method of Example 6 using the polyprenol mixture inwhich n distributes between 11 and 19 obtained in Example 2, was usedinstead of the polyprenyl acetate in which n is 15. There were obtained4.72 g of a colorless clear liquid.

By high-performance liquid chromatography using Li Chrosorb RP 18-10(C₁₈ type) (a semipreparative high-performance liquid chromatographycolumn made by Merck Co.), a mixture of acetone and methanol (90/10) asan eluent, and a differential refractometer as a detector, nine mainpeaks were observed. The ratio of the existance of each component wascalculated from the area ratio of this chromatogram. The results areshown below.

    ______________________________________                                                              Ratio of                                                Peak No.  n           existence                                                                              FD-MASS                                        ______________________________________                                        1         11          0.3      1040                                           2         12          1.0      1108                                           3         13          5.9      1176                                           4         14          25.7     1244                                           5         15          39.6     1312                                           6         16          19.3     1380                                           7         17          5.7      1448                                           8         18          1.7      1516                                           9         19          0.8      1584                                           ______________________________________                                    

The individual fractions were separated by using the same liquidchromatography, and subjected to FD-MASS analysis. It was confirmed thatthe respective peaks are attributed to n=11-19. The fractions separatedaccording to the respective peaks were analyzed by IR, ¹ H-NMR and ¹³C-NMR, and it was confirmed that the product was the compound of generalformula (V) in which n is 11 to 19, and Z is --CH₂ OH. The compound inwhich n is 15 and which corresponded to peak No. 5 showed quite the sameanalytical values as the compound obtained in Example 31. The compoundscorresponded to the other peaks showed absorption signals in IR, ¹ H-NMRand ¹³ C-NMR at the same positions as the compound corresponded to peakNo. 5 with some differences in intensity ratios. The resulting liquidproduct had a specific rotation of [α]_(D) ²⁰ =+0.51° (neat).

EXAMPLE 67

Example 31 was repeated except that(R)-2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran ([α]_(D) ²⁰ =-3.61°,c=4.0, chloroform) synthesized by using (R)-4-bromo-3-methylbutanol inaccordance with the method described at the end of Example 31 was usedinstead of the 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, and thesame polyprenyl acetate mixture as used in Example 66 was used insteadof the polyprenyl acetate (n=15). Thus, 5.52 g of a colorless clearliquid was obtained. The liquid was analyzed by high-performance liquidchromatography under the same conditions as in Example 66. The resultswere the same as in Example 66. The results of its FD-MASS, IR ¹ H-NMRand ¹³ C-NMR analyses were also the same as in Example 66. The liquidproduct had a specific rotation of [α]_(D) ²⁰ =-0.51° (neat).

What we claim is:
 1. A polyprenyl composition consisting essentially ofa mixture of polyprenyl compounds represented by the following formula:##STR69## wherein A₁ represents a hydroxyl or acetyloxy group, ##STR70##represents a transisoprene unit, ##STR71## represents a cisisopreneunit, and n is an integer of from 11-19, said mixture containing, basedon the total weight of the mixture, at least 20% by weight of thecompound of formula (I) wherein n is 14, at least 30% by weight of thecompound of formula (I) wherein n is 15, and at least 10% by weight ofthe compound of formula (I) wherein n is 16; the total amount of thesethree compounds being at least 70% by weight based on the weight of themixture of the polyprenyl compound of formula (I) in which the integer nvaries from 11-19.
 2. The composition of claim 1 which contains acompound of formula (I) in which n is 15 in the highest content.
 3. Thecomposition of claim 1 which contains 30 to 50% by weight, based on theweight of the mixture, of a compound of formula (I) in which n is
 15. 4.The composition of claim 1 which contains 20 to 35% by weight of acompound of formula (I) in which n is 14 and 10 to 25% by weight of acompound of formula (I) in which n is 16, both based on the weight ofthe mixture.
 5. The composition of claim 1 wherein the total amount of acompound of formula (I) in which n is 14, a compound of formula (I) inwhich n is 15, and a compound of formula (I) in which n is 16 is atleast 75% by weight based on the weight of the mixture.
 6. Thecomposition of claim 1 which contains the compounds of formula (I) inthe following contents:

    ______________________________________                                        n         content (% by weight)                                               ______________________________________                                        11        0-3                                                                 12        0.1-6                                                               13        4-17                                                                14        20-35                                                               15        30-50                                                               16        10-25                                                               17        2-10                                                                18        0.1-5                                                               19        0-3                                                                 ______________________________________                                    


7. The composition of claim 1 wherein the average of n is 14.25 to15.25.
 8. The composition according to claim 1 in which said polyprenylmixture contains, based on the weight of the mixture, 20 to 35% byweight of the compound of formula (I) wherein n is 14, 30 to 50% byweight of the compound of formula (I) wherein n is 15, and 10-25% byweight of the compound of formula (I) wherein n is
 16. 9. Thecomposition of claim 1, in which the mixture contains, based on theweight of the mixture, a % by weight of the compound of formula (I)wherein n is 14, b % by weight of the compound of formula (I) wherein nis 15 and c % of the compound of formula (I) wherein n is 16, the valuesa, b and c satisfying the following quantitative relationship:

    20≦a≦35,

    30≦b≦50,

    10≦c≦25,

    a+b+c≧70 and

    b>a>c.


10. The composition of claim 9, in which

    23≦a≦32,

    32≦b≦47, and

    11≦c≦20.